Composite shaped bodies and methods for their production and use

ABSTRACT

Shaped, composite bodies are provided. One portion of the shaped bodies comprises an RPR-derived porous inorganic material, preferably a calcium phosphate. Another portion of the composite bodies is a different solid material, preferably metal, glass, ceramic or polymeric. The shaped bodies are especially suitable for orthopaedic and other surgical use.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.09/373,796, the contents of which are incorporated herein by referencein their entirety.

FIELD OF THE INVENTION

This invention relates to the preparation of composite shaped bodies,especially those having at least a portion comprising a calciumphosphate-containing material. This invention also relates to methodsfor preparing the bodies and to methods for use thereof. In accordancewith certain embodiments of this invention, shaped bodies are providedwhich are at once, possessed of two or more portions having differentproperties. In accordance with other preferred embodiments, at least oneportion of the composite is highly porous and uniform in composition.The shaped bodies can be produced in a wide range of geometricconfigurations through novel, low temperature techniques. The shapedbodies of the invention can have portions which are highly and uniformlyporous while being self-supporting. They can be strengthened furtherusing a variety of techniques, thereby forming porous compositestructures. Such composite structures are useful as cell growthscaffolds, bone grafting materials, drug delivery vehicles, biologicalseparation/purification media, catalysis and other supports and in awide range of other uses. One of the most preferred uses for thecomposite structures of this invention is in the field of orthopaedic,restorative and reconstructive surgery. Thus, the present inventionprovides shaped bodies having highly suitable combinations of propertieswhich make those bodies extraordinarily useful for bone replacement,spinal repair, reconstructive, cosmetic and other surgeries.

BACKGROUND OF THE INVENTION

There has been a continuing need for improved methods for thepreparation of mineral compositions, especially calciumphosphate-containing minerals. This long-felt need is reflected in partby the great amount of research found in the pertinent literature. Whilesuch interest and need stems from a number of industrial interests, thedesire to provide materials which closely mimic mammalian bone for usein repair and replacement of such bone has been a major motivatingforce. Such minerals are principally calcium phosphate apatites as foundin teeth and bones. For example, type-B carbonated hydroxyapatite[Ca5(PO4)3-x(CO3)x(OH)] is the principal mineral phase found in thebody, with variations in protein and organic content determining theultimate composition, crystal size, morphology, and structure of thebody portions formed therefrom.

Calcium phosphate ceramics have been fabricated and implanted in mammalsin various forms including, but not limited to, shaped bodies andcements. Different stoichiometric compositions such as hydroxyapatite(HAp), tricalcium phosphate (TCP), tetracalcium phosphate (TTCP), andother calcium phosphate salts and minerals, have all been employed tothis end in an attempt to match the adaptability, biocompatibility,structure, and strength of natural bone. The role of pore size andporosity in promoting revascularization, healing, and remodeling of boneis now recognized as a critical property for bone replacement materials.Despite tremendous efforts directed to the preparation of porous calciumphosphate materials for such uses, significant shortcomings stillremain. This invention overcomes those shortcomings and describes porouscalcium phosphate and a wide variety of other inorganic materials which,in the case of calcium phosphates, closely resemble bone, and methodsfor the fabrication of such materials as shaped bodies for biological,chemical, industrial, and many other applications.

Early ceramic biomaterials exhibited problems derived from chemical andprocessing shortcomings that limited stoichiometric control, crystalmorphology, surface properties, and, ultimately, reactivity in the body.Intensive milling and comminution of natural minerals of varyingcomposition was required, followed by powder blending and ceramicprocessing at high temperatures to synthesize new phases for use invivo.

A number of patents have issued which relate to ceramic biomaterials andare incorporated herein by reference. Among these are U.S. Pat. No.4,880,610, B. R. Constantz, “In situ calcium phosphate minerals—methodand composition;” U.S. Pat. No. 5,047,031, B. R. Constantz, “In situcalcium phosphate minerals method;” U.S. Pat. No. 5,129,905, B. R.Constantz, “Method for in situ prepared calcium phosphate minerals;”U.S. Pat. No. 4,149,893, H. Aoki, et al, “Orthopaedic and dental implantceramic composition and process for preparing same;” U.S. Pat. No.4,612,053, W. E. Brown, et al, “Combinations of sparingly solublecalcium phosphates in slurries and pastes as mineralizers and cements;”U.S. Pat. No. 4,673,355, E. T. Farris, et al, “Solid calcium phosphatematerials;” U.S. Pat. No. 4,849,193, J. W. Palmer, et al., “Process ofpreparing hydroxyapatite;” U.S. Pat. No. 4,897,250, M. Sumita, “Processfor producing calcium phosphate;” U.S. Pat. No. 5,322,675, Y.Hakamatsuka, “Method of preparing calcium phosphate;” U.S. Pat. No.5,338,356, M. Hirano, et al “Calcium phosphate granular cement andmethod for producing same;” U.S. Pat. No. 5,427,754, F. Nagata, et al.,“Method for production of platelike hydroxyapatite;” U.S. Pat. No.5,496,399, I. C. Ison, et al., “Storage stable calcium phosphatecements;” U.S. Pat. No. 5,522,893, L. C. Chow. et al., “Calciumphosphate hydroxyapatite precursor and methods for making and usingsame;” U.S. Pat. No. 5,545,254, L. C. Chow, et al., “Calcium phosphatehydroxyapatite precursor and methods for making and using same;” U.S.Pat. No. 3,679,360, B. Rubin, et al., “Process for the preparation ofbrushite crystals;” U.S. Pat. No. 5,525,148, L. C. Chow, et al.,“Self-setting calcium phosphate cements and methods for preparing andusing them;” U.S. Pat. No. 5,034,352, J. Vit, et al., “Calcium phosphatematerials;” and U.S. Pat. No. 5,409,982, A. Imura, et al “Tetracalciumphosphate-based materials and process for their preparation.”

Several patents describe the preparation of porous inorganic or ceramicstructures using polymeric foams impregnated with a slurry of preformedceramic particles. These are incorporated herein by reference: U.S. Pat.No. 3,833,386, L. L. Wood, et al, “Method of preparing porous ceramicstructures by firing a polyurethane foam that is impregnated withinorganic material;” U.S. Pat. No. 3,877,973, F. E. G. Ravault,“Treatment of permeable materials;” U.S. Pat. No. 3,907,579, F. E. G.Ravault, “Manufacture of porous ceramic materials;” and U.S. Pat. No.4,004,933, F. E. G. Ravault, “Production of porous ceramic materials.”However, none of aforementioned art specifically describes thepreparation of porous metal or calcium phosphates and none employs themethods of this invention.

The prior art also describes the use of solution impregnated-polymericfoams to produce porous ceramic articles and these are incorporatedherein by reference: U.S. Pat. No. 3,090,094, K. Schwartzwalder, et al,“Method of making porous ceramic articles;” U.S. Pat. No. 4,328,034 C.N. Ferguson, “Foam Composition and Process;” U.S. Pat. No. 4,859,383, M.E. Dillon, “Process of Producing a Composite Macrostructure of Organicand Inorganic Materials;” U.S. Pat. No. 4,983,573, J. D. Bolt, et al,“Process for making 90° K superconductors by impregnating cellulosicarticle with precursor solution;” U.S. Pat. No. 5,219,829, G. Bauer, etal, “Process and apparatus for the preparation of pulverulent metaloxides for ceramic compositions;” GB 2,260,538, P. Gant, “Porousceramics;” U.S. Pat. No. 5,296,261, J. Bouet, et al, “Method ofmanufacturing a sponge-type support for an electrode in anelectrochemical cell;” U.S. Pat. No. 5,338,334, Y. S. Zhen, et al,“Process for preparing submicron/nanosize ceramic powders fromprecursors incorporated within a polymeric foam;” and S. J. Powell andJ. R. G. Evans, “The structure of ceramic foams prepared frompolyurethane-ceramic suspensions,” Materials & Manufacturing Processes,10(4):757 (1995). The focus of this art is directed to the preparationof either metal or metal oxide foams and/or particles. None of thedisclosures of these aforementioned references mentions in situ solidphase formation via redox precipitation reaction from homogeneoussolution as a formative method.

The prior art also discloses certain methods for fabricating, inorganicshaped bodies using natural, organic objects. These fabrication methods,however, are not without drawbacks which include cracking upon dryingthe green body and/or upon firing. To alleviate these problems, thefabrication processes typically involve controlled temperature andpressure conditions to achieve the desired end product. In addition,prior fabrication methods may include the additional steps of extensivematerial preparation to achieve proper purity, particle sizedistribution and orientation, intermediate drying and radiation steps,and sintering at temperatures above the range desired for employment inthe present invention. For example, U.S. Pat. No. 5,298,205 issued toHayes et. al. entitled “Ceramic Filter Process”, incorporated herein byreference, discloses a method of fabricating a porous ceramic body froman organic sponge saturated in an aqueous slurry comprised of gluten andparticulate ceramic material fired at a temperature range from 1,100° to1,300° C. Hayes teaches that the saturated sponge must be dehydratedprior to firing via microwave radiation, and includes a pre-soak heatingstep, and a hot pressing step.

While improvements have been made in materials synthesis and ceramicprocessing technology leading to porous ceramics and ceramicbiomaterials, improved preparative methods, and the final products thesemethods yield, are still greatly desired. Generation of controlledporosity in ceramic biomaterials generally, and in calcium phosphatematerials in particular, is crucial to the effective in vitro and invivo use of these synthetic materials for regenerating human cells andtissues. This invention provides both novel, porous calcium phosphatematerials and methods for preparing them. Methods relating to calciumphosphate-containing biomaterials, which exhibit improved biologicalproperties, are also greatly desired despite the great efforts of othersto achieve such improvements.

In particular, this invention provides such novel, porous calciumphosphate and other materials in composite forms, especially in shapedbodies. Thus, the benefits of these novel materials are now enhancedthrough combining into such shaped bodies areas of the novel materialsalong with areas or portions comprising other materials.

Accordingly, it is a principal object of this invention to provideimproved inorganic, porous, shaped bodies, especially those formed ofcalcium phosphate.

Such shaped bodies having a plurality of portions, one of whichcomprises the novel, inorganic, porous materials of this invention arealso provide by this invention.

Another object is to provide shaped bodies for surgical, orthopaedic,reconstructive and restorative uses.

A further object of the invention is to provide methods for forming suchmaterials with improved yields, lower processing temperatures, greatercompositional flexibility, and better control of porosity.

Yet another object provides materials with micro-, meso-, andmacroporosity, as well as the ability to generate shaped porous solidshaving improved uniformity, biological activity, catalytic activity, andother properties.

Another object is to provide porous materials which are useful in therepair and/or replacement of bone in orthopaedic and dental procedures.

An additional object is to prepare a multiplicity of high purity,complex shaped objects, formed at temperatures below those commonly usedin traditional firing methods.

Further objects will become apparent from a review of the presentspecification.

SUMMARY OF THE INVENTION

The present invention is directed to new inorganic bodies, especiallycontrollably porous bodies, which can be formed into virtually anygeometric shape. The novel preparative methods of the invention utilizeredox precipitation chemistry or aqueous solution chemistry, which isdescribed in pending U.S. patent application Ser. No. 08/784,439assigned to the present assignee and, incorporated herein by reference.In accordance with certain preferred embodiments, the redoxprecipitation chemistry is utilized in conjunction with a sacrificial,porous cellular support, such as an organic foam or sponge, to produce aporous inorganic product which faithfully replicates both the bulkgeometric form as well as the macro-, meso-, and microstructure of theprecursor organic support. The aqueous solution, because of its uniquechemistry, has a high solids equivalent, yet can essentially be imbibedfully into and infiltrate thoroughly the microstructure of thesacrificial organic precursor material. This extent of infiltrationallows the structural details and intricacies of the precursor organicfoam materials to be reproduced to a degree heretofore unattainable.This great improvement can result in porous, inorganic materials havingnovel microstructural features and sufficient robustness to be handledas coherent bodies of highly porous solid.

The invention also gives rise to porous inorganic materials havingimproved compositional homogeneity, multiphasic character, and/ormodified crystal structures at temperatures far lower than thoserequired in conventional formation methods. In addition, the inventionalso gives rise to porous inorganic composites comprising mineralscaffolds strengthened and/or reinforced with polymers, especiallyfilm-forming polymers, such as gelatin.

The present invention is also directed to composite shaped bodiescomprising two or more portions. One of the portions is the reactionproduct of a metal cation and an oxidizing agent together with aprecursor anion oxidizable by the oxidizing agent. The reaction is onewhich gives rise to at least on gaseous product. Another portion of thecomposite shaped bodies of the invention is another solid. Such solidmay be any of a wide range of materials such as metal, especiallytitanium, stainless steel and other surgical metals, ceramic, glass,polymer or other generally hard material. The composite shaped bodiesare ideally suited for surgical use, especially in orthopaedics and inreconstructive and restorative surgery. The porous materials forming oneportion of the composite bodies of the invention are high compatiblewith such surgical use and can give rise to osteogenesis orosteostimulation in some cases. This is especially true of calciumphosphate materials.

The new paradigm created by this invention is facilitated by adefinition of terms used in the description of embodiments. The generalmethod starts with infiltrant solutions produced from raw materialsdescribed herein as salts, aqueous solutions of salts, stable hydrosolsor other stable dispersions, and/or inorganic acids. The sacrificial,porous organic templates used in some embodiments may be organic foams,cellular solids and the like, especially open-cell hydrophilic materialwhich can imbibe the aqueous infiltrant solutions. Both the precursororganic templates, as well as the inorganic replicas produced inaccordance within this invention, display a porosity range of at least 3orders of magnitude. This range of porosity can be described as macro-,meso- and microporous. Within the scope of this invention, macroporosityis defined as having a pore diameter greater than or equal to 100microns, mesoporosity is defined as having a pore diameter less than 100microns but greater than or equal to 10 microns, and microporosity isdefined as having a pore diameter less than 10 microns.

In addition to the controlled macro-, meso- and microporosity ranges,inorganic shaped bodies have been fabricated possessing pore volumes ofat least about 30%. In preferred embodiments, pore volumes of over 50%have been attained and pore volumes in excess of 70% or 80% are mQrepreferred. Materials having macro-, meso- and microporosity togetherwith pore volumes of at least about 90% can be made as can those havingpore volumes over 92% and even 94%. In some cases, pore volumesapproaching 95% have been ascertained in products which, nevertheless,retain their structural integrity and pore structure.

The phases produced by the methods of this invention [RedoxPrecipitation Reaction (RPR) and HYdrothermal PROCESSING (HYPR)]initially are intermediate or precursor minerals, which can be easilyconverted to a myriad of pure and multiphasic minerals of previouslyknown and, in some cases, heretofore undefined stoichiometry, generallyvia a thermal treatment under modest firing regimens compared to knownand practiced conventional art.

In accordance with certain embodiments of the present invention, methodsare provided for the restoration of bony tissue. In this regard, an areaof bony tissue requiring repair as a result of disease, injury, desiredreconfiguration and the like, is identified and preferably measured. Ablock of porous calcium phosphate material can be made to fit thedimensions of the missing or damaged bony tissue and implanted in placeby itself or in conjunction with biocompatible bonding materialcompositions such as those disclosed in U.S. Pat. No. 5,681,872 issuedin the name of E. M. Erbe on Oct. 28, 1997 and incorporated herein byreference. The calcium phosphate material can also be used as a “sleeve”or form for other implants, as a containment vessel for the bonegrafting material which is introduced into the sleeve for the repair,and in many other contexts.

A major advantage of the restoration is that after polymerization, ithas a significant, inherent strength, such that restoration ofload-bearing bony sites can be achieved. While immobilization of theeffected part will likely still be required, the present inventionpermits the restoration of many additional bony areas than has beenachievable heretofore. Further, since the porous calcium phosphatescaffolding material of the present invention is biocompatible and,indeed, bioactive, osteogenesis can occur. This leads to boneinfiltration and replacement of the calcium phosphate matrix withautologous bone tissue.

The calcium phosphate scaffolding material of the present invention mayalso be made into shaped bodies for a variety of uses. Thus, orthopaedicappliances such as joints, rods, pins, or screws for orthopaedicsurgery, plates, sheets, and a number of other shapes may be formed fromthe material in and of itself or used in conjunction with conventionalappliances that are known in the art. Such hardened compositions can bebioactive and can be used, preferably in conjunction with hardenablecompositions in accordance with the present invention in the form ofgels, pastes, or fluids, in surgical techniques. Thus, a screw or pincan be inserted into a broken bone in the same way that metal screws andpins are currently inserted, using conventional bone cements orrestoratives in accordance with the present invention or otherwise. Thebioactivity of the present hardenable materials give rise toosteogenesis, with beneficial medical or surgical results.

The methods of the invention are energy efficient, being performed atrelatively low temperature; have high yields; and are amenable tocareful control of product shape, macro- and microstructure, porosity,and chemical purity. Employment as bioactive ceramics is a principal,anticipated use for the materials of the invention, with improvedproperties being extant. Other uses of the porous minerals and processesfor making the same are also within the spirit of the invention.

The present invention also provides exceptionally fine, uniform powdersof inorganic materials. Such powders have uniform morphology, uniformcomposition and narrow size distribution. They may be attained throughthe comminution of shaped bodies in accordance with the invention andhave wide utility in chemistry, industry, medicine and otherwise.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an aggregated physical structure of an RPR generated,multiphasic β-tricalcium phosphate (β-TCP)+type-B carbonated apatite(c-HAp) [β-Ca3(PO₄)2+Ca5(PO4)3-x(CO3)×(OH)] prepared in accordance withone embodiment of this invention. The entire agglomerated particle isapproximately 10 μm, and the individual crystallites are typically lessthan about 1 μm and relatively uniform in particle size and shape.

FIG. 2 represents assembled monetite, CaHPO₄ particles formed from ahydrothermal precipitation in accordance with certain methods taught bythis invention. The entire particle assemblage is typically about 30 μmand is comprised of relatively uniformly rectangular cubes andplate-like crystallites of various sizes and aspect ratios.

FIG. 3 illustrates a water purification disk that is comprised of theporous inorganic material of the present invention and is containedwithin an exterior housing for filtration or separation purposes.

FIG. 4 illustrates shaped bodies of porous inorganic material of thepresent invention used as a catalyst support within a hot gas reactor ordiffusor.

FIG. 5 illustrates shaped bodies of porous calcium phosphate material ofthe present invention implanted at several sites within a human femurfor cell seeding, drug delivery, protein adsorption, or growth factorscaffolding purposes.

FIG. 6A and FIG. 6B illustrate one embodiment of porous calciumphosphate scaffolding material of the present invention used as anaccommodating sleeve in which a tooth is screwed, bonded, cemented,pinned, anchored, or otherwise attached in place.

FIGS. 7 and 7A illustrate another embodiment of the porous calciumphosphate scaffolding material of the present invention used as acranio-maxillofacial, zygomatic reconstruction and mandibular implant.

FIGS. 8A and 8B illustrate one embodiment of the porous calciumphosphate scaffolding material of the present invention shaped into ablock form and used as a tibial plateau reconstruction that is screwed,bonded, cemented, pinned, anchored, or otherwise attached in place.

FIG. 9 illustrates an embodiment of the porous calcium phosphatescaffolding material of the present invention shaped into a block orsleeve form and used for the repair or replacement of bulk defects inmetaphyseal bone, oncology defects or screw augmentation.

FIGS. 10A and 10B illustrate an embodiment of the porous calciumphosphate scaffolding material of the present invention shaped into asleeve form and used for impaction grafting to accommodate an artificialimplant said sleeve form being screwed, bonded, pinned or otherwiseattached in place.

FIG. 11 is an X-ray diffraction (XRD) plot of a pulverized sample ofporous calcium phosphate material fired at 500° C. in accordance withone embodiment of this invention. The sample consists of a biphasicmixture of whitlockite Ca₃(PO₄)₂ (PDF 09-0169) and hydroxyapatiteCa₅(PO₄)₃(OH) (PDF 09-0432).

FIG. 12 is a 50× magnification scanning electron micrograph of a virgincellulose sponge material used to prepare several of the embodiments ofthis invention.

FIG. 13 is a 100× magnification scanning electron micrograph of porouscalcium phosphate material fired at 500° C. in accordance with oneembodiment of this invention.

FIG. 14 is an X-ray diffraction (XRD) plot of a pulverized sample ofporous calcium phosphate material fired at 1100° C. in accordance withone embodiment of this invention. The sample consists of whitlockiteCa₃(PO₄)₂ (PDF 09-0169).

FIG. 15 is an X-ray diffraction (XRD) plot of a pulverized sample ofporous calcium phosphate material fired at 1350° C. in accordance withone embodiment of this invention. The sample consists of whitlockiteCa₃(PO₄)₂ (PDF 09-0169).

FIG. 16 is an X-ray diffraction (XRD) plot of a pulverized sample ofporous calcium phosphate material fired at 800° C. in accordance withone embodiment of this invention. The sample consists of calciumpyrophosphate, Ca₂P₂O₇ (PDF 33-0297).

FIG. 17 is an X-ray diffraction (XRD) plot of a pulverized sample ofporous zinc phosphate material fired at 500° C. in accordance with oneembodiment of this invention. The sample consists of zinc phosphate,Zn₃(PO₄)₂ (PDF 30-1490).

FIG. 18 is an X-ray diffraction (XRD) plot of a pulverized sample ofporous neodymium phosphate material fired at 500° C. in accordance withone embodiment of this invention. The sample consists of neodymiumphosphate, NdPO₄ (PDF 25-1065).

FIG. 19 is an X-ray diffraction (XRD) plot of a pulverized sample ofporous aluminum phosphate material fired at 500° C. in accordance withone embodiment of this invention. The sample consists of aluminumphosphate, AlPO₄ (PDF 11-0500).

FIG. 20 is a 23× magnification scanning electron micrograph depictingthe macro- and meso-porosity of porous calcium phosphate material firedat 500° C. and reinforced with gelatin in accordance with one embodimentof this invention.

FIG. 21 is a 25× magnification scanning electron micrograph of sheeptrabecular bone for comparative purposes.

FIG. 22 is a 2000× magnification scanning electron micrograph of theair-dried gelatin treated inorganic sponge depicted in FIG. 20 whichexhibits meso- and microporosity in the calcium phosphate matrix. FIGS.20 and 22, together, demonstrate the presence of macro-, meso-, andmicroporosity simultaneously in a highly porous product

FIG. 23 is an X-ray diffraction (XRD) plot of a pulverized sample of theash remaining after firing at 500° C. of the virgin cellulose spongestarting material used to prepare several of the embodiments of thisinvention. The ash sample consists of a biphasic mixture of magnesiumoxide, MgO (major) (PDF 45-0946) and sodium chloride, NaCl (minor) (PDF05-0628).

FIG. 24 is a 20× magnification scanning electron micrograph of a virgincellulose sponge starting material, expanded from its compressed state,used to prepare several of the embodiments of this invention.

FIG. 25 is a 20× magnification scanning electron micrograph of porouscalcium phosphate material fired at 800° C. and reinforced with gelatinin accordance with one embodiment of this invention.

FIG. 26 depicts a calcium phosphate porous body, produced in accordancewith one embodiment of this invention partially wicked with blood.

FIG. 27 shows a cylinder of calcium phosphate prepared in accordancewith one embodiment of this invention, implanted into the metaphysealbone of a canine.

FIG. 28 is an X-ray diffraction plot of a pulverized sample of a cationsubstituted hydroxyapatite material processed in accordance with themethods described in this invention.

FIG. 29 depicts a synthetic cortical vertebral ring inserted between apair of vertebrae in a spine. The injection of hardenable material, suchas bone cement, into a port in the cortical ring is shown.

FIG. 30 is a lateral view of a synthetic cortico-cancellous vertebralring or interbody fusion device. The composite nature of the device isshown to comprise first and second portions comprising differentmaterials.

FIGS. 31 through 34 all depict spinal surgical applications withvertebrae depicted in phantom, 220.

FIG. 31 shows one embodiment of a synthetic cortical bone dowel inplace. The dowel has a plurality of ports, some of which are shown 224.

FIG. 32 depicts another bone dowel for spinal fusion.

FIG. 33 shows a synthetic cortical interbody vertebral defect fillingform.

FIG. 34 shows a cross section of a spinal fusion employing a shaped bodyof the invention potted in hardenable material.

FIGS. 35 a, 35 b and 35 c depict synthetic cortical vertebral spacers orinterbody devices. FIGS. 35 b and 35 c are in the shape of rings.

FIGS. 36 a through c depict synthetic cortical bone dowels or interbodydevices.

FIG. 37 is another form of cortical spacer.

FIG. 38 is of a synthetic cancellous bone dowel.

FIG. 39 is a synthetic cortical vertebral interbody device.

FIGS. 40 a, and 40 c are of synthetic cortico-cancellous defect fillingforms for bone restoration. FIG. 40 b shows a cancellous defect fillingform.

FIGS. 41 a and 41 b are drawn to bone dowels.

FIG. 42 is a synthetic cortical ring

FIG. 43 is a cortical rod for orthopaedic restoration

FIG. 44 is a synthetic cortico-cancellous “tri-cortical” device

FIG. 45 depicts a cortico-cancellous “crouton” for orthopaedic surgery.

FIG. 46 is a “match stick” orthopaedic surgical splint.

FIGS. 47 a and 47 b are cortical struts for surgical use.

FIGS. 48, 49, 50 a and 50 b are cortical rings.

FIG. 51 depicts an artificial femur head for reconstructive surgery.

FIG. 52 is an artificial bone portion

FIG. 53 is a strut or tube for reconstruction.

FIG. 54 is an acetabular/pelvic form for orthopaedic reconstruction.

FIGS. 55 a and b depict insertion of a femoral hip dowel into a femur.

FIGS. 56 a through d are different forms of dowels for orthopaedic use.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In accordance with this invention, composite shaped bodies are providedwhich are useful, e.g. in orthopaedic and other surgery. The bodies havea first portion which is a solid and which is attached to, adhered to,coformed with or in contact with a second portion. The second portion isreaction product of a blend comprising at least one metal cation atleast one oxidizing agent; and at least one precursor anion oxidizableby said oxidizing agent to form an oxoanion. The reaction gives rise toat least one gaseous product and is generally of the type of reactionknown as oxidation-reduction reactions. This results in what is termedan RPR-derived material. The resulting composite shaped bodies may beformed into nearly any shape, including shapes useful in orthopaedic andother surgery, especially when the RPR-derived material is a calciumphosphate.

The RPR-derived material is usually arrived at in two stages. Thus, aprecursor mineral is formed from an immediate oxidation-reductionreaction, and then that material is consolidated or transformed into afinal calcium phosphate or other material. In accordance with thepresent invention, methods are provided for preparing shapes comprisingan intermediate precursor mineral of at least one metal cation and atleast one oxoanion. These methods comprise preparing an aqueous solutionof the metal cation and at least one oxidizing agent. The solution isaugmented with at least one soluble precursor anion oxidizable by saidoxidizing agent to give rise to the precipitant oxoanion. Theoxidation-reduction reaction thus contemplated is conveniently initiatedby heating the solution under conditions of temperature and pressureeffective to give rise to said reaction. In accordance with preferredembodiments of the invention, the oxidation-reduction reaction causes atleast one gaseous product to evolve and the desired intermediateprecursor mineral to precipitate from the solution.

The intermediate precursor mineral thus prepared can either be used “asis” or can be treated in a number of ways. Thus, it may be heat treatedin accordance with one or more paradigms to give rise to a preselectedcrystal structure or other preselected morphological structures therein.In accordance with preferred embodiments, the oxidizing agent is nitrateion and the gaseous product is a nitrogen oxide, generically depicted asNO_(x(g)). It is preferred that the precursor mineral provided by thepresent methods be substantially homogeneous. It is also preferred formany embodiments that the temperature reached by the oxidation-reductionreaction not exceed about 150° C. unless the reaction is run underhydrothermal conditions or in a pressure vessel.

In accordance with other preferred embodiments, the intermediateprecursor mineral provided by the present invention is a calciumphosphate. It is preferred that such mineral precursor comprise, inmajor proportion, a solid phase which cannot be identified singularlywith any conventional crystalline form of calcium phosphate. At the sametime, the calcium phosphate mineral precursors of the present inventionare substantially homogeneous and do not comprise a physical admixtureof naturally occurring or conventional crystal phases.

In accordance with preferred embodiments, the low temperature processesof the invention lead to the homogeneous precipitation of high puritypowders from highly concentrated solutions. Subsequent modest heattreatments convert the intermediate material to e.g. novel monophasiccalcium phosphate minerals or novel biphasic β-tricalcium phosphate(β-TCP)+type-B, carbonated apatite (c-HAp)[β-Ca₃(PO₄)₂+Ca₅(PO₄)_(3-x)(CO₃)_(x)(OH)] particulates.

In other preferred embodiments, calcium phosphate salts are providedthrough methods where at least one of the precursor anions is aphosphorus oxoanion, preferably introduced as hypophosphorous acid or asoluble alkali or alkaline-earth hypophosphite salt. For the preparationof such calcium phosphates, it is preferred that the initial pH bemaintained below about 3, and still more preferably below about 1.

The intermediate precursor minerals prepared in accordance with thepresent methods are, themselves, novel and not to be expected from priormethodologies. Thus, such precursor minerals can be, at once,non-stoichiometric and possessed of uniform morphology.

It is preferred in connection with some embodiments of the presentinvention that the intermediate precursor minerals produced inaccordance with the present methods be heated, or otherwise treated, tochange their properties. Thus, such materials may be heated totemperatures as low as 300° C. up to about 800° C. to give rise tocertain beneficial transformations. Such heating will remove extraneousmaterials from the mineral precursor, will alter its composition andmorphology in some cases, and can confer upon the mineral a particularand preselected crystalline structure. Such heat treatment can be totemperatures which are considerably less than those used conventionallyin accordance with prior methodologies to produce end product mineralphases. Accordingly, the heat treatments of the present invention donot, necessarily, give rise to the “common” crystalline morphologies ofmonetite, dicalcium or tricalcium phosphate, tetracalcium phosphate,etc., but, rather, they can lead to new and unobvious morphologies whichhave great utility in the practice of the present invention.

The present invention is directed to the preparation, production and useof shaped bodies of inorganic materials. It will be appreciated thatshaped bodies can be elaborated in a number of ways, which shaped bodiescomprise an inorganic material. A preferred method for giving rise tothe shaped bodies comprising minerals is through the use of subjectmatter disclosed in United State Ser. No. 08/784,439 filed Jan. 16,1997, assigned to the assignee of the present invention and incorporatedherein by reference. In accordance with techniques preferred for use inconjunction with the present invention, a blend of materials are formedwhich can react to give rise to the desired mineral, or precursorthereof, at relatively low temperatures and under relatively flexiblereaction conditions. Preferably, the reactive blends thus used includeoxidizing agents and materials which can be oxidized by the oxidizingagent, especially those which can give rise to a phosphorus oxoanion.Many aspects of this chemistry are described hereinafter in the presentspecification. It is to be understood, however, that such reactiveblends react at modest temperatures under modest reaction conditions,usually through the evolution of a nitrogen oxide gas, to give rise tothe minerals desired for preparation or to materials which may betransformed such as through heating or sintering to form such minerals.A principal object of the present invention is to permit such mineralsto be formed in the form of shaped bodies.

It will be appreciated that preferred compositions of this inventionexhibit high degrees of porosity. It is also preferred that the porosityoccur in a wide range of effective pore sizes. In this regard, personsskilled in the art will appreciate that preferred embodiments of theinvention have, at once, macroporosity, mesoporosity and microporosity.Macroporosity is characterized by pore diameters greater than about 100μm. Mesoporosity is characterized by pore diameters between about 100and 10 μm, while microporosity occurs when pores have diameters belowabout 10 μm. It is preferred that macro-, meso- and microporosity occursimultaneously in products of the invention. It is not necessary toquantify each type of porosity to a high degree. Rather, persons skilledin the art can easily determine whether a material has each type ofporosity through examination, such as through the preferred method ofscanning electron microscopy. While it is certainly true that more thanone or a few pores within the requisite size range are needed in orderto characterize a sample as having a substantial degree of thatparticular form of porosity, no specific number or percentage is calledfor. Rather, a qualitative evaluation by persons skilled in the artshall be used to determine macro-, meso- and microporosity.

It is preferred that the overall porosity of materials prepared inaccordance with this invention be high. This characteristic is measuredby pore volume, expressed as a percentage. Zero percent pore volumerefers to a fully dense material, which, perforce, has no pores at all.One hundred percent pore volume cannot meaningfully exist since the samewould refer to “all pores” or air. Persons skilled in the art understandthe concept of pore volume, however and can easily calculate and applyit. For example, pore volume may be determined in accordance with W. D.Kingery, Introduction to Ceramics, 1960 p. 416 (Wiley, 1060), whoprovides a formula for determination of porosity. Expressing porosity asa percentage yields pore volume. The formula is: Pore Volume=(1-f_(p))100%, where fp is fraction of theoretical density achieved.

Pore volumes in excess of about 30% are easily achieved in accordancewith this invention while materials having pore volumes in excess of 50or 60% are also routinely attainable. It is preferred that materials ofthe invention have pore volumes of at least about 75%. More preferredare materials having pore volumes in excess of about 85%, with 90% beingstill more preferred. Pore volumes greater than about 92% are possibleas are volumes greater than about 94%. In some cases, materials withpore volumes approaching 95% can be made in accordance with theinvention. In preferred cases, such high pore volumes are attained whilealso attaining the presence of macro-meso- and microporosity as well asphysical stability of the materials produced. It is believed to be agreat advantage to be able to prepare inorganic shaped bodies havingmacro-, meso- and microporosity simultaneously with high pore volumes asdescribed above.

It has now been found that such shaped bodies may be formed fromminerals in this way which have remarkable macro- and microstructures.In particular, a wide variety of different shapes can be formed andbodies can be prepared which are machinable, deformable, or otherwisemodifiable into still other, desired states. The shaped bodies havesufficient inherent physical strength allowing that such manipulationcan be employed. The shaped bodies can also be modified in a number ofways to increase or decrease their physical strength and otherproperties so as to lend those bodies to still further modes ofemployment. Overall, the present invention is extraordinarily broad inthat shaped mineral bodies may be formed easily, inexpensively, undercarefully controllable conditions, and with enormous flexibility.Moreover, the microstructure of the materials that can be formed fromthe present invention can be controlled as well, such that they may becaused to emulate natural bone, to adopt a uniform microstructure, to berelatively dense, relatively porous, or, in short, to adopt a widevariety of different forms. The ability to control in a predictable andreproducible fashion the macrostructure, microstructure, and mineralidentity of shaped bodies in accordance with the present invention underrelatively benign conditions using inexpensive starting materials lendsthe technologies of the present invention to great medical, chemical,industrial, laboratory, and other uses.

In accordance with certain preferred embodiments of the presentinvention, a reactive blend in accordance with the invention is causedto be imbibed into a material which is capable of absorbing it. It ispreferred that the material have significant porosity, be capable ofabsorbing significant amounts of the reactive blend via capillaryaction, and that the same be substantially inert to reaction with theblend prior to its autologous oxidation-reduction reaction. It has beenfound to be convenient to employ sponge materials, especially cellulosesponges of a kind commonly found in household use for this purpose.Other sponges, including those which are available in compressed formsuch as Normandy sponges, are also preferred in certain embodiments. Thesubstrate used to imbibe the reactive blend, however, are not limited toorganic materials and can include inorganic materials such asfiberglass.

The sponges are caused to imbibe the reactive blend in accordance withthe invention and are subsequently, preferably blotted to remove excessliquid. The reactive blend-laden sponge is then heated to whateverdegree may be necessary to initiate the oxidation-reduction reaction ofthe reactive blend. Provision is generally made for the removal ofby-product noxious gases, chiefly nitrogen oxide gases, from the site ofthe reaction. The reaction is exothermic, however the entire reactedbody does not generally exceed a few hundred degrees centigrade. In anyevent, the reaction goes to completion, whereupon what is seen is anobject in the shape of the original sponge which is now intimatelycomprised of the product of the oxidation reduction reaction. Thismaterial may either be the finished, desired mineral, or may be aprecursor from which the desired product may be obtained by subsequentPROCESSING.

Following the initial oxidation-reduction reaction, it is convenientand, in many cases, preferred to heat treat the reacted product so as toeliminate the original sponge. In this way, the cellulosic component ofthe sponge is pyrolyzed in a fugitive fashion, leaving behind only themineral and in some cases, a small amount of ash. The resulting shapedbody is in the form of the original sponge and is self-supporting. Assuch, it may be used without further transformation or it may be treatedin one or more ways to change its chemical and or physical properties.Thus, the shaped body following the oxidation-reduction reaction, can beheat treated at temperatures of from about 250° C. to about 1400° C.,preferably from 500° C. to about 1000° C., and still more preferablyfrom about 500° C. to about 800° C. Thus, a precursor mineral formedfrom the oxidation-reduction reaction may be transformed into the finalmineral desired for ultimate use. A number of such transformations aredescribed in the examples to the present application and still otherswill readily occur to persons skilled in the art.

It will be appreciated that temperatures in excess of 250° C. may beemployed in initiating the oxidation-reduction reaction and, indeed, anyconvenient temperature may be so utilized. Moreover, methods ofinitiating the reaction where the effective temperature is difficult orimpossible to determine, such a microwave heating, may also be employed.The preferred procedures, however, are to employ reaction conditions toinitiate, and propagate if necessary, the reaction are below thetemperature wherein melting of the products occur. This is indistinction with conventional glass and ceramic processing methods.

The shaped bodies thus formed may be used in a number of ways directlyor may be further modified. Thus, either the as-formed product of theoxidation-reduction reaction may be modified, or a resulting,transformed mineral structure may be modified, or both. Various naturaland synthetic polymers, pre-polymers, organic materials, metals andother adjuvants may be added to the inorganic structures thus formed.Thus, wax, glycerin, gelatin, pre-polymeric materials such as precursorsto various nylons, acrylics, epoxies, polyalkylenes, and the like, maybe caused to permeate all or part of the shaped bodies formed inaccordance with the present invention. These may be used to modify thephysical and chemical nature of such bodies. In the case of polymers,strength modifications may easily be obtained. Additionally, suchmaterials may also change the chemical nature of the minerals, such asby improving their conductivity, resistance to degradation, electrolyticproperties, electrochemical properties, catalytic properties, orotherwise. All such modifications are contemplated by the presentinvention.

As will be appreciated, the shaped bodies prepared in accordance withthe present invention may be formed in a very large variety of shapesand structures. It is very easy to form cellulose sponge material intodiffering shapes such as rings, rods, screw-like structures, and thelike. These shapes, when caused to imbibe a reactive blend, will giverise to products which emulate the original shapes. It is alsoconvenient to prepare blocks, disks, cones, frustrums or other grossshapes in accordance with the present invention which shapes can bemachined, cut, or otherwise manipulated into a final desiredconfiguration. Once this has been done, the resulting products may beused as is or may be modified through the addition of gelatin, wax,polymers, and the like, and used in a host of applications.

When an inherently porous body such as a sponge is used as a substratefor the imbibition of reactive blend and the subsequent elaboration ofoxidation-reduction product, the resulting product replicates the shapeand morphology of the sponge. Modifications in the shape of the sponge,and in its microstructure can give rise to modifications in at least theintermediate structure and gross structures of the resulting products.It has been found, however, that the microstructure of shaped bodiesprepared in accordance with the present invention frequently includecomplex and highly desirable features. Thus, on a highly magnifiedscale, microstructure of materials produced in accordance with thepresent invention can show significant microporosity. In severalembodiments of the present invention, the microstructure can becustom-tailored based upon the absorbent material selected as thefugitive support. One particular embodiment, which used a kitchen spongeas the absorbent material, exhibited a macro- and microstructure similarto the appearance of ovine trabecular bone. This highly surprising, yethighly desirable result gives rise to obvious benefits in terms of thereplication of bony structures and to the use of the present inventionin conjunction with the restoration of bony tissues in animals andespecially in humans.

Other macro- and microstructures may be attained through the presentinvention, however. Thus, through use of the embodiments of the presentinvention, great diversity may be attained in the preparation of mineralstructures not only on a macroscopic but also on a microscopic level.Accordingly, the present invention finds utility in a wide variety ofapplications. Thus, the shaped bodies may be used in medicine, forexample for the restoration of bony defects and the like. The materialsmay also be used for the delivery of medicaments internal to the body.In this way, the porosity of a material formed in accordance with theinvention may be all or partially filled with another material whicheither comprises or carries a medicament such as a growth hormone,antibiotic, cell signaling material, or the like. Indeed, the largerporous spaces within some of the products of the present invention maybe used for the culturing of cells within the human body. In thisregard, the larger spaces are amenable to the growth of cells and can bepermeated readily by bodily fluids such as certain blood components. Inthis way, growing cells may be implanted in an animal through the aegisof implants in accordance with the present invention. These implants maygive rise to important biochemical or therapeutic or other uses.

The present invention can call for the use of therapeutic materials.Replicated bone marrow or other types of bioengineered bone marrowmaterial can be used in this invention. Therapeutic materials can alsobe used for the delivery of healing materials, such as medicaments,internal to the body. Such medicaments can be growth hormones,antibiotics, or cell signals. Medicaments also may include steroids,analgesics, or fertility drugs. Exemplary therapeutic materials includesignaling molecules under the Transforming Growth Factor (TGF)Superfamily of proteins, specifically proteins under the TGF-beta(TGF-β), Osteogenic Protein (OP)/Bone Morphogenic Protein (BMP), VEGF(VEGF-1 and VEGF-2 proteins) and Inhibin/activtin (Inhibin-beta A,Inhibin-beta B, Inhibin-alpha, and MIS proteins) subfamilies. Mostpreferably, the exemplary therapeutic materials are proteins under theTGF-β and OP/BMP subfamilies. The TGF-β subfamily includes the proteinsBeta-2, Beta-3, Beta-4 (chicken), Beta-1, Beta-5 (xenopus) and HIF-1alpha. The OP/BMP subfamily includes the proteins BMP-2, BMP-4, DPP,BMP-5, Vgr-1, OP-1/BMP-7, Drosophila 60A, GDF-1, Xenopus Vg-1 and BMP-3.Representative proteins of these types include: OP-1/rhBMP-7, rhBMP-2,IGF-1 (Insulin-like Growth Factor-1), TGF beta, MP52. Other proteins,genes and cells outside the TGF Superfamily may also be included in theexemplary types of therapeutic materials to be used in conjunction withthe present invention. These other proteins, genes and cells includePepGen P-15, LMP-1 (LIM Mineralized Protein-1 gene), Chrysalin TP 508Synthetic Peptide, GAM (parathyroid hormone), rhGDF-5, cell lines andFGF (Fibroblast Growth Factor) such as BFGF (Basic Fibroblast GrowthFactor), FGF-A (Fibroblast Growth Factor Acidic), FGFR (FibroblastGrowth Factor Receptor) and certain cell lines such as osteosarcoma celllines. The therapeutic materials to be used with the present inventionmaterial may also be combinations of those listed above. Such mixturesinclude products like Ne-Osteo GFm (growth factor mixture), or mixturesof growth factors/proteins/genes/cells produced by devices such as AGF(Autologous Growth Factor), Symphony Platelet Concentrate System, andthe like.

The invention finds great utility in chemistry as well. Shaped bodiesformed from the present invention may be formed to resemble saddles,rings, disks, honeycombs, spheres, tubes, matrixes, and, in short, ahuge array of shapes, which shapes may be used for engineering purposes.Thus, such shapes may be made from minerals which incorporate catalyticcomponents such as rare earths, precious and base metals, palladium,platinum, Raney nickel and the like for catalytic use. These shapes mayalso be used for column packing for distillation and other purposes.Indeed, the shapes may be capable of serving a plurality of uses atonce, such as being a substrate for refluxing while acting as a catalystat the same time.

The bodies of the present invention will also be suitable forchromatography and other separation and purification techniques. Thus,they may serve as substrates for mobile phases in the same way that acapillary suspends a gelatinous material for capillary gelelectrophoresis.

The present invention also provides filtration media. As is apparent,the porous structures of the present invention may serve as filters. Dueto the ability to formulate these shaped bodies in a wide variety ofcarefully controlled ways, some unique structures may be attained. Thus,an anisotropic membrane, as known to persons of ordinary skill in theart, and frequently referred to as a “Michaels” membrane may be used forthe imbibation of reactive blend in accordance with the invention.Following redox reaction and removal of the membranous material as afugitive phase, the resulting inorganic structure is also anisotropic.It is thus possible to utilize materials and shaped bodies in accordancewith the present invention as an anisotropic but inorganic filtrationmedia. Since it is also possible to include a number of inorganicmaterials therein, such filters may be caused to be inherentlybacteriostatic and non-fouling. It has been shown, heretofore, thatanisotropic membranes such as polysulfone and other membranes arecapable of nurturing and growing cells for the purposes of deliveringcellular products into a reaction screen. It is now possible toaccomplish the same goals using wholly inorganic structures prepared inaccordance with this invention.

In addition to the foregoing, it is possible to prepare and modifyshaped bodies in accordance with the present invention in a variety ofother ways. Thus, the shaped bodies may be coated, such as with apolymer. Such polymers may be any of the film forming polymers orotherwise and may be used for purposes of activation, conductivity,passivation, protection, or other chemical and physical modification.The bodies may also be contacted with a “keying agent” such as a silane,or otherwise to enable the grafting of different materials onto thesurface of the polymer.

The shaped bodies of the invention may also be used for the growth ofoligomers on their surfaces. This can be done in a manner analogous to aMerrifield synthesis, an oligonucleotide synthesis or otherwise. Suchshaped bodies may find use in conjunction with automated syntheses ofsuch oligomers and may be used to deliver such oligomers to the body ofan animal, to an assay, to a synthetic reaction vessel, or otherwiseSince the mineral composition of the shaped bodies of this invention maybe varied so widely, it is quite suitable to the elaboration ofoligomers as suggested here and above. Grafting of other inorganicmaterials, silanes, especially silicones and similar materials, is aparticular feature of the present invention. The grafting reactions,keying reactions, oligomer extension reactions and the like are allknown to persons skilled in the art and will not be repeated here.Suffice it to say that all such reactions are included within the scopeof the present invention.

The shaped bodies of the invention may also be coated through surfacelayer deposition techniques such as plasma coating, electroless plating,chemical vapor deposition (CVD), physical vapor deposition (PVD), orother methods. In such a way, the surface structure of the shaped bodiesmay be modified in carefully controlled ways for catalytic, electronic,and other purposes. The chemistry and physics of chemical vapordeposition and other coating techniques are known to persons of ordinaryskill in the art whose knowledge is hereby assumed.

In accordance with other embodiments of the invention, the shaped bodiesproduced hereby may be comminuted to yield highly useful and uniquepowder materials finding wide utility. Thus, shaped bodies may becrushed, milled, etc. and preferably classified or measured, such aswith a light scattering instrument, to give rise to fine powders. Suchpowders are very small and highly uniform, both in size, shape andchemical composition. Particles may be prepared having particle sizenumber means less than about 0.1 μm or 100 nanometers. Smaller meansized may also be attained. Thus, this invention provides highly uniforminorganic materials in powder form having particle sizes, measured bylight scattering techniques such that the number mean size is betweenabout 0.1 and 5.0 μm. Particle sizes between about 0.5 and 2.0 μm mayalso be attained. It may, in some embodiments, be desired to classifythe powders in order to improve uniformity of size.

The morphology of the particles is highly uniform, deriving, it isthought, from the microporosity of the shaped bodies from which theyarise. The particles are also highly uniform chemically. Since theyarise from a chemical reaction from a fully homogenous solution, suchuniformity is much greater than is usually found in glass or ceramicmelts.

Particle size number means are easily determined with a Horiba LA-910instrument. Number means refers to the average or mean number ofparticles having the size or size range in question.

Such powders are very useful, finding use in cosmetics, pharmaceuticals,excipients, additives, pigments, fluorescing agents, fillers, flowcontrol agents, thixotropic agents, materials processing, radiolabels,and in may other fields of endeavor. For example, a molded golf ball mayeasily be made such as via the processes of Bartsch, including a calciumphosphate powder of this invention admixed with a crosslinked acrylicpolymer system.

In conjunction with certain embodiments of the present invention,shaping techniques are employed on the formed, shaped bodies of thepresent invention. Thus, such bodies may be machined, pressed, stamped,drilled, lathed, or otherwise mechanically treated to adopt a particularshape both externally and internally. As will be appreciated, theinternal microstructure of the bodies of the present invention can bealtered thru the application of external force where such modificationsare desired. Thus, preforms may be formed in accordance with theinvention from which shapes may be cut or formed. For example, anorthopaedic sleeve for a bone screw may be machined from a block ofcalcium phosphate made hereby, and the same tapped for screw threads orthe like. Carefully controllable sculpting is also possible such thatprecisely-machined shapes may be made for bioimplantation and otheruses.

While many of the present embodiments rely upon the imbibation ofreactive blends by porous, organic media such as sponges and the like,it should be appreciated that many other ways of creating shaped bodiesin accordance with this invention also exist. In some of theseembodiments, addition of materials, either organic or inorganic, whichserve to modify the characteristic of the reactive blend may bebeneficial. As an example of this, flow control agents may be employed.Thus, it may be desirable to admix a reactive blend in accordance withthe invention together with a material such as a carboxymethyl or othercellulose or another binding agent to give rise to a paste or slurry.This paste or slurry may then be formed and the oxidation reductionreaction initiated to give rise to particular shapes. For example,shaped bodies may be formed through casting, extrusion, foaming, doctorblading, spin molding, spray forming, and a host of other techniques. Itis possible to extrude hollow shapes in the way that certain forms ofhollow pasta are extruded. Indeed, machinery useful for the preparationof certain food stuffs may also find beneficial use in conjunction withcertain embodiments of the present invention. To this end, foodextrusion materials such as that used for the extrusion of “cheesepuffs” or puffed cereals may be used. These combine controllabletemperature and pressure conditions with an extrusion apparatus. Throughcareful control of the physical conditions of the machinery, essentiallyfinished, oxidation-reduction product may be extruded and used as-is orin subsequently modified form.

In accordance with certain embodiments, a film of reactive blend may bedoctored onto a surface, such as stainless steel or glass, and the filmcaused to undergo an oxidation-reduction reaction. The resultingmaterial can resemble a potato chip in overall structure with variableporosity and other physical properties.

In addition to the use of sponge material, the present invention is alsoamenable to the use of other organic material capable of imbibingreactive blend. Thus, if a gauze material is used, the resultingoxidation reduction product assumes the form of the gauze. A flannelmaterial will give rise to a relatively thick pad of inorganic materialfrom which the organic residue may be removed through the application ofheat. Cotton or wool may be employed as may be a host of other organicmaterials.

It is also possible to employ inorganic materials and even metals inaccordance with the present invention. Thus, inclusion of conductivemesh, wires, or conductive polymers in materials which form thesubstrate for the oxidation reduction of the reactive blend can giverise to conductive, mineral-based products. Since the minerals may beformed or modified to include a wide variety of different elements, thesame may be caused to be catalytic. The combination of a porous,impermeable, catalytic material with conductivity makes the presentinvention highly amenable to use in fuel cells, catalytic converters,chemical reaction apparatus and the like.

In this regard, since the conductive and compositional character of theshaped bodies of the present invention may be varied in accordance withpreselected considerations, such shapes may be used in electronic andmilitary applications. Thus, the ceramics of the invention may bepiezoelectric, may be transparent to microwave radiation and, hence,useful in radomes and the like. They may be ion responsive and,therefore, useful as electrochemical sensors, and in many other ways.The materials of the invention may be formulated so as to act aspharmaceutical excipients, especially when comminuted, as gas scrubbermedia, for pharmaceutical drug delivery, in biotechnologicalfermentation apparatus, in laboratory apparatus, and in a host of otherapplications.

As will be apparent from a review of the chemistry portion of thepresent specification, a very large variety of mineral species may beformed. Each of these may be elaborated into shaped bodies as describedhere and above. For example, transition metal phosphates including thoseof scandium, titanium, chromium, manganese, iron, cobalt, nickel,copper, and zinc may be elaborated into pigments, phosphors, catalysts,electromagnetic couplers, microwave couplers, inductive elements,zeolites, glasses, and nuclear waste containment systems and coatings aswell as many others.

Rare earth phosphates can form intercalation complexes, catalysts,glasses, ceramics, radiopharmaceuticals, pigments and phosphors, medicalimaging agents, nuclear waste solidification media, electro-opticcomponents, electronic ceramics, surface modification materials and manyothers. Aluminium and zirconium phosphates, for example, can give riseto surface protection coatings, abrasive articles, polishing agents,cements, filtration products and otherwise.

Alkali and alkaline earth metal phosphates are particularly amenable tolow temperature glasses, ceramics, biomaterials, cements, glass-metalsealing materials, glass-ceramic materials including porcelains, dentalglasses, electro-optical glasses, laser glasses, specific refractiveindex glasses, optical filters and the like.

In short, the combination of easy fabrication, great variability inattainable shapes, low temperature elaboration, wide chemicalcomposition latitude, and the other beneficial properties of the presentinvention lend it to a wide variety of applications. Indeed, otherapplications will become apparent as the full scope of the presentinvention unfolds over time.

In accordance with the present invention, the minerals formed hereby andthe shaped bodies comprising them are useful in a wide variety ofindustrial, medical, and other fields. Thus, calcium phosphate mineralsproduced in accordance with preferred embodiments of the presentinvention may be used in dental and orthopaedic surgery for therestoration of bone, tooth material and the like. The present mineralsmay also be used as precursors in chemical and ceramic processing, andin a number of industrial methodologies, such as crystal growth, ceramicprocessing, glass making, catalysis, bioseparations, pharmaceuticalexcipients, gem synthesis, and a host of other uses. Uniformmicrostructures of unique compositions of minerals produced inaccordance with the present invention confer upon such minerals wideutility and great “value added.” Indeed, submicron microstructure can beemployed by products of the invention with the benefits which accompanysuch microstructures.

Improved precursors provided by this invention yield lower formationtemperatures, accelerated phase transition kinetics, greatercompositional control, homogeneity, and flexibility when used inchemical and ceramic processes. Additionally, these chemically-derived,ceramic precursors have fine crystal size and uniform morphology withsubsequent potential for very closely resembling or mimicking naturaltissue structures found in the body.

Controlled precipitation of specific phases from aqueous-solutionscontaining metal cations and phosphate anions represents a difficulttechnical challenge. For systems containing calcium and phosphate ions,the situation is further complicated by the multiplicity of phases thatmay be involved in the crystallization reactions as well as by thefacile phase transformations that may proceed during mineralization. Thesolution chemistry in aqueous systems containing calcium and phosphatespecies has been scrupulously investigated as a function of pH,temperature, concentration, anion character, precipitation rate,digestion time, etc. (P. Koutsoukos, Z. Amjad, M. B. Tomson, and G. H.Nancollas, “Crystallization of calcium phosphates. A constantcomposition study,” J. Am. Chem. Soc. 102: 1553 (1980); A. T. C. Wong.and J. T. Czemuszka, “Prediction of precipitation and transformationbehavior of calcium phosphate in aqueous media,” in Hydroxyapatite andRelated Materials, pp 189-196 (1994), CRC Press, Inc.; G. H. Nancollas,“In vitro studies of calcium phosphate crystallization,” inBiomineralization —Chemical and Biochemical Perspectives, pp 157-187(1989)).

Solubility product considerations impose severe limitations on thesolution chemistry. Furthermore, methods for generating specific calciumphosphate phases have been described in many technical articles andpatents (R. Z. LeGeros, “Preparation of octacalcium phosphate (OCP): Adirect fast method,” Calcif. Tiss. Int. 37: 194 (1985)). As discussedabove, none of this aforementioned art employs the present invention.

Several sparingly soluble calcium phosphate crystalline phases, socalled “basic” calcium phosphates, have been characterized, includingalpha- and beta-tricalcium phosphate (α-TCP, β-TCP, Ca₃(PO₄)₂),tetracalcium phosphate (TTCP, Ca₄(PO₄)₂O), octacalcium phosphate (OCP,Ca₄H(PO₄)₃.-nH₂O, where 2<n<3), and calcium hydroxyapatite (HAp,Ca₅(PO₄)₃(OH)). Soluble calcium phosphate phases, so called “acidic”calcium phosphate crystalline phases, include dicalcium phosphatedihydrate (brushite-DCPD, CaHPO₄.H₂O), dicalcium phosphate anhydrous(monetite-DCPA, CaHPO₄), monocalcium phosphate monohydrate (MCPM, Ca(H₂PO₄)₂—H₂O), and monocalcium phosphate anhydrous (MCPA, Ca(H₂ PO₄)₂).These calcium phosphate compounds are of critical importance in the areaof bone cements and bone grafting materials. The use of DCPD, DCPA,α-TCP, β-TCP, TTCP, OCP, and HAp, alone or in combination, has been welldocumented as biocompatible coatings, fillers, cements, and bone-formingsubstances (F. C. M. Driessens, M. G. Boltong, O. Bermudez, J. A.Planell, M. P. Ginebra, and E. Fernandez, “Effective formulations forthe preparation of calcium phosphate bone cements,” J. Mat. Sci.: Mat.Med. 5: 164 (1994); R. Z. LeGeros, “Biodegradation and bioresorption ofcalcium phosphate ceramics,” Clin. Mat. 14(1): 65 (1993); K. Ishikawa,S. Takagi, L. C. Chow, and Y. Ishikawa, “Properties and mechanisms offast-setting calcium phosphate cements,” J. Mat. Sci.: Mat. Med. 6: 528(1995); A. A. Mirtchi, J. Lemaitre, and E. Munting, “Calcium phosphatecements: Effect of fluorides on the setting and hardening ofbeta-tricalcium phosphate-dicalcium phosphate-calcite cements,” Biomat.12: 505 (1991); J. L. Lacout, “Calcium phosphate as bioceramics,” inBiomaterials—Hard Tissue Repair and Replacement, pp 81-95 (1992),Elsevier Science Publishers).

Generally, these phases are obtained via thermal or hydrothermalconversion of (a) solution-derived precursor calcium phosphatematerials, (b) physical blends of calcium salts, or (c) natural coral.Thermal transformation of synthetic calcium phosphate precursorcompounds to TCP or TTCP is achieved via traditional ceramic processingregimens at high temperature, greater than about 800° C. Thus, despitethe various synthetic pathways for producing calcium phosphateprecursors, the “basic” calcium phosphate materials used in the art(Ca/P>1.5) have generally all been subjected to a high temperaturetreatment, often for extensive periods of time. For other preparationsof “basic” calcium phosphate materials, see also H. Monma, S. Ueno, andT. Kanazawa, “Properties of hydroxyapatite prepared by the hydrolysis oftricalcium phosphate,” J. Chem. Tech. Biotechnol. 31: 15 (1981); H.Chaair, J. C. Heughebaert, and M. Heughebaert, “Precipitation ofstoichiometric apatitic tricalcium phosphate prepared by a continuousprocess,” J. Mater. Chem. 5(6): 895 (1995); R. Famery, N. Richard, andP. Boch, “Preparation of alpha- and beta-tricalcium phosphate ceramics,with and without magnesium addition,” Ceram. Int. 20: 327 (1994); Y.Fukase, E. D. Eanes, S. Takagi, L. C. Chow, and W. E. Brown, “Settingreactions and compressive strengths of calcium phosphate cements,” J.Dent. Res. 69(12): 1852 (1990).

The present invention represents a significant departure from priormethods for synthesizing metal phosphate minerals and porous shapedbodies of these materials, particularly calcium phosphate powders andmaterials, in that the materials are formed from homogeneous solutionusing a novel Redox Precipitation Reaction (RPR). They can besubsequently converted to TCP, HAp and/or combinations thereof at modesttemperatures and short firing schedules. Furthermore, precipitation fromhomogeneous solution (PFHS) in accordance with this invention, has beenfound to be a means of producing particulates of uniform size andcomposition in a form heretofore not observed in the prior art.

The use of hypophosphite [H₂PO₂ ⁻] anion as a precursor to phosphate iongeneration has been found to be preferred since it circumvents many ofthe solubility constraints imposed by conventional calcium phosphateprecipitation chemistry and, furthermore, it allows for uniformprecipitation at high solids levels. For example, reactions can beperformed in accordance with the invention giving rise to productslurries having in excess of 30% solids. Nitrate anion is the preferredoxidant, although other oxidizing agents are also useful.

The novel use of nitrate anion under strongly acidic conditions as theoxidant for the hypophosphite to phosphate reaction is beneficial fromseveral viewpoints. Nitrate is readily available and is an inexpensiveoxidant. It passivates stainless steel (type 316 SS) and is non-reactiveto glass processing equipment. Its oxidation byproducts (NO_(x)) aremanageable via well-known pollution control technologies, and anyresidual nitrate will be fugitive, as NO_(x) under the thermalconversion schedule to which the materials are usually subjected, thusleading to exceedingly pure final materials.

Use of reagent grade metal nitrate salts and hypophosphorous acid, aspracticed in this invention, will lead to metal phosphate phases ofgreat purity.

Methods for producing useful calcium phosphate-based materials areachieved by reduction-oxidation precipitation reactions (RPR) generallyconducted at ambient pressure and relatively low temperatures, usuallybelow 250° C. and preferably below 200° C., most preferably below 150°C. The manner of initiating such reactions is determined by the startingraw materials, their treatment, and the redox electrochemicalinteractions among them.

The driving force for the RPR is the concurrent reduction and oxidationof anionic species derived from solution precursors. Advantages of thestarting solutions can be realized by the high initial concentrations ofionic species, especially calcium and phosphorus species. It has beenfound that the use of reduced phosphorus compounds leads to solutionstability at ionic concentrations considerably greater than if fullyoxidized [PO₄]-3 species were used. Conventional processing art usesfully oxidized phosphorus oxoanion compounds and is, consequently,hindered by pH; solubility, and reaction temperature constraints imposedby the phosphate anion.

Typical reducible species are preferably nitric acid, nitrate salts(e.g. Ca(NO₃)₂4H₂O), or any other reducible nitrate compound, which ishighly soluble in water. Other reducible species include nitrous acid(HNO₂) or nitrite (NO₂ ⁻) salts.

Among the oxidizable species which can be used are hypophosphorous acidor hypophosphite salts [e.g. Ca(H₂PO₂)₂] which are highly soluble inwater. Other oxidizable species which find utility include acids orsalts of phosphites (HPO₃ ²⁻), pyrophosphites (H₂P₂O₅ ²⁻), thiosulfate(S₂O₃ ²⁻), tetrathionate (S₄O₆ ²⁻), dithionite (S₂O₄ ²⁻) trithionate(S₃O₆ ²⁻), sulfite (SO₃ ²⁻), and dithionate (S₂O₆ ²⁻). In considerationof the complex inorganic chemistry of the oxoanions of Groups 5B, 6B,and 7B elements, it is anticipated that other examples of oxidizableanions can be utilized in the spirit of this invention.

The cation introduced into the reaction mixture with either or both ofthe oxidizing or reducing agents are preferably oxidatively stable (i.e.in their highest oxidation state). However, in certain preparations, orto effect certain reactions, the cations may be introduced in apartially reduced oxidation state. Under these circumstances, adjustmentin the amount of the oxidant will be necessary in order to compensatefor the electrons liberated during the oxidation of the cations duringRPR.

It is well known in the art that for solutions in equilibrium with ionicprecipitates, the solute concentrations of the reactant ions aredictated by solubility product relationships and supersaturationlimitations. For the Ca²⁺—[PO₄]⁻³ system, these expressions areexceedingly complicated, due in large part to the numerous pathways(i.e., solid phases) for relieving the supersaturation conditions.Temperature, pH, ionic strength, ion pair formation, the presence ofextraneous cations and anions all can affect the various solute speciesequilibria and attainable or sustainable supersaturation levels (F.Abbona, M. Franchini-Angela, and R. Boistelle, “Crystallization ofcalcium and magnesium phosphates from solutions of medium and lowconcentrations,” Cryst. Res. Technol. 27: 41 (1992); G. H. Nancollas,“The involvement of calcium phosphates in biological mineralization anddemineralization processes,” Pure Appl. Chem. 64(11): 1673 (1992); G. H.Nancollas and J. Zhang, “Formation and dissolution mechanisms of calciumphosphates in aqueous systems,” in Hydroxyapatite and Related Materials,pp 73-81 (1994), CRC Press, Inc.; P. W. Brown, N. Hocker, and S. Hoyle,“Variations in solution chemistry during the low temperature formationof hydroxyapatite,” J. Am. Ceram. Soc. 74(8): 1848 (1991); G. Vereeckeand J. Lemaitre, “Calculation of the solubility diagrams in the systemCa(OH)₂—H₃PO₄— KOH−HNO₃—CO₂—H₂O,” J. Cryst. Growth 104: 820 (1990); A.T. C. Wong and J. T. Czemuszka, “Prediction of precipitation andtransformation behavior of calcium phosphate in aqueous media,” inHydroxyapatite and Related Materials, pp 189-196 (1994), CRC Press,Inc.; G. H. Nancollas, “In vitro studies of calcium phosphatecrystallization,” in Biomineralization—Chemical and BiochemicalPerspectives, pp 157-187 (1989)).

Additionally, while thermodynamics will determine whether a particularreaction is possible, kinetic effects may be very much more important inexplaining the absence or presence of particular calcium phosphatephases during precipitation reactions.

In the practice of certain preferred embodiments of this invention togive rise to calcium phosphates, soluble calcium ion is maintained atconcentrations of several molar in the presence of soluble hypophosphiteanion which is, itself, also at high molar concentrations. The solutionis also at a very low pH due to the presence of nitric andhypophosphorous acids. Indeed, such solutions of calcium andhypophosphite ions can be stable indefinitely with respect toprecipitation, at room temperature or below. In contrast, it isimpossible (in the absence of ion complexation or chelating agents) tosimultaneously maintain calcium ions and phosphate anions at similarconcentrations as a solid phase would immediately precipitate to relievethe supersaturation. Upon oxidation of the hypophosphite ion tophosphite and, subsequently, to phosphate, calcium phosphate phases arerapidly precipitated from homogeneous solution under solution conditionsunique (concentration, pH, ionic strength) for the formation of suchmaterials. The combination of homogeneous generation of precipitatinganion, rapid precipitation kinetics, and unique thermodynamic regimeresults in the formation of calcium phosphate precursors having uniquesize and morphological characteristics, surface properties, andreactivities.

The foregoing consideration will also apply to minerals other than thecalcium phosphates. Perforce, however, the phase diagrams, equilibriumconditions and constituent mineral phases will differ in each family ofminerals.

Uniformly sized and shaped particles of metal salts comprised of one ormore metal cations in combination with one or more oxoacid anions canresult from the present general method for the controlled precipitationof said metal salts from aqueous solutions. These proceed via the insitu homogeneous production of simple or complex oxoacid anions of oneor more of the nonmetallic elements, Group 5B and 6B (chalcogenides),and 7B (halides). The first oxoacid anion undergoes oxidation (increasein chemical oxidation state) to generate the precipitant anionic speciesalong with concurrent reduction (decrease in chemical oxidation state)of the nonmetallic element of a second, dissimilar oxoacid anion, alloxoacid anions initially being present in solution with one or moremetal cations known to form insoluble salts with the precipitant anion.The metal cations are, preferably, oxidatively stable, but may undergooxidation state changes themselves under certain conditions.

RPR is induced preferably by heating a homogeneous solution, so as topromote the onset and continuation of an exothermic redox reaction. Thisexothermic reaction results in the generation of gases, usually variousnitrogen oxide gases such as NO_(x), where 0.5<x<2, as the solublereduced phosphorus species are converted to precipitating anions whichthen homogeneously precipitate the calcium ions from the reactionmedium. At this stage, the reaction is substantially complete, resultingin an assemblage of ultrafine precipitated particles of thepredetermined calcium-phosphate stoichiometry. The reaction yield ishigh as is the purity of the reaction products.

The use of alternate heating methods to initiate and complete the RPRreaction may offer utility in the formation of scaffold structures. Onesuch power source is microwave energy, as found in conventional 600-1400W home microwave ovens. The benefit of the use of microwaves is theuniformity of the heating throughout the entire reaction mass and volumeas opposed to the external-to-internal, thermal gradient created fromtraditional conduction/convection/radiant heating means. The rapid,internal, uniform heating condition created by the use of microwaveenergy provides for rapid redox reaction initiation and drying. Theexcess RPR liquid is expelled to the outer surface of the cellulose bodyand flashes off to form an easily removed deposit on the surface. Therapid rate of heating and complete removal of the fugitive substructurealters the particulate structure resulting in greater integral strength.The speed of heating and initiation of the RPR reaction may alsominimize crystal grain growth. Intermediate precursor mineral powdersare homogeneously precipitated from solution. Moderate heat treatmentsat temperatures <500° C., can be used to further the transformation tovarious phosphate containing phases. Proper manipulations of chemistryand process conditions have led to mono- and multiphasic compounds withunique crystal morphologies, see, e.g. FIGS. 1 and 2.

The nitrate/hypophosphite redox system involves a hypophosphiteoxidation to phosphate (P⁺¹ to P⁺⁵, a 4e⁻ oxidation) as depicted in thefollowing equations (E_(o)/V from N. N. Greenwood and A. Earnshaw,“Oxoacids of phosphorus and their salts,” in Chemistry of the Elements,pp 586-595 (1984), Pergamon Press): Reduction potential at pH 0, 25° C.Reaction E_(o)/V H₃PO₃ + 2H⁺ + 2e⁻ = H₃PO₂ + H₂O −0.499 (1) H₃PO₄ =2H⁺ + 2e⁻ = H₃PO₃ + H₂O −0.276 (2) H₃PO₄ + 4H⁺ + 4e⁻ = H₃PO₂ + H₂O−0.775 Overall (3)

and a nitrate reduction to NO_(x)(N⁺⁵ to N⁺³ or N⁺², either a 2e⁻ or a3e⁻ reduction) as depicted in the following equations: Reductionpotential at pH 0, 25° C. Reaction E_(o)/V 2NO₃ ⁻ + 4H⁺ + 2e⁻ = N₂O₄ +2H₂O 0.803 (4) NO₃ ⁻ + 3H⁺ + 2e⁻ = HNO₂ + H₂O 0.94  (5) NO₃ + 4H⁺ + 3e⁻= NO + 2H₂O 0.957 (6)

Chemical reactions are conveniently expressed as the sum of two (ormore) electrochemical half-reactions in which electrons are transferredfrom one chemical species to another. According to electrochemicalconvention, the overall reaction is represented as an equilibrium inwhich the forward reaction is stated as a reduction (addition ofelectrons), i.e.:Oxidized species+ne ⁻=Reduced species

For the indicated equations at pH=0 and 25° C., the reaction isspontaneous from left to right if E_(o) (the reduction potential) isgreater than 0, and spontaneous in the reverse direction if E_(o) isless than 0.

From the above reactions and associated electrochemical potentials, itis apparent that nitrate is a strong oxidant capable of oxidizinghypophosphite (P⁺¹) to phosphite (P⁺³) or to phosphate P⁺⁵) regardlessof the reduction reaction pathway, i.e., whether the reduction processoccurs according to Equation 4, 5, or 6. If an overall reaction pathwayis assumed to involve a combination of oxidation reaction (Eq.3) (4e⁻exchange) and reduction reaction (Eq.6) (3e⁻ exchange), one cancalculate that in order for the redox reaction to proceed to completion,4/3 mole of NO₃— must be reduced to NO per mole of hypophosphite ion toprovide sufficient electrons. It is obvious to one skilled in the artthat other redox processes can occur involving combinations of thestated oxidation and reduction reactions.

Different pairings of oxidation and reduction reactions can be used togenerate products according to the spirit of this invention. Indeed, theinvention generally allows for the in situ homogeneous production ofsimple or complex oxoacid anions in aqueous solution in which one ormore nonmetallic elements such as Group 5B and 6B (chalcogenides), and7B (halides) comprising the first oxoacid anion undergoes oxidation togenerate the precipitant anionic species along with concurrent reductionof the nonmetallic element of a second, dissimilar oxoacid anion.

In each of the above scenarios, the key is the reduction-oxidationreaction at high ionic concentrations leading to the homogenousprecipitation from solution of novel calcium phosphate powders. Neverbefore in the literature has the ability to form such phases, especiallycalcium-phosphate phases, been reported under the conditions describedin this invention.

Specific embodiments of the invention utilize the aforementionedprocesses to yield unique calcium phosphate precursor minerals that canbe used to form a self-setting cement or paste. Once placed in the body,these calcium phosphate cements (CPC) will be resorbed and remodeled(converted) to bone. A single powder consisting of biphasic minerals ofvarying Ca/P ratio can be mixed to yield self-setting pastes thatconvert to type-B carbonated apatite (bone mineral precursor) in vivo.

The remodeling behavior of a calcium phosphate bioceramic to bone isdictated by the energetics of the surface of the ceramic and theresultant interactions with osteoclastic cells on approach to theinterface. Unique microstructures can yield accelerated reactivity and,ultimately, faster remodeling in vivo. The compositional flexibility inthe fine particles of this invention offers adjustable reactivity invivo. The crystallite size and surface properties of the resultantembodiments of this invention are more similar to the scale expected andfamiliar to the cells found in the body. Mixtures of powders derivedfrom the processes of this invention have tremendous utility as calciumphosphate cements (CPCs).

An aqueous solution can be prepared in accordance with the presentinvention and can be imbibed into a sacrificial organic substrate ofdesired shape and porosity, such as a cellulose sponge. Thesolution-soaked substrate is subjected to controlled temperatureconditions to initiate the redox precipitation reaction. After the redoxprecipitation reaction is complete, a subsequent heating step isemployed to combust any remaining organic material and/or promote phasechanges. The resultant product is a porous, inorganic material whichmimics the shape, porosity and other aspects of the morphology of theorganic substrate.

It is anticipated that the porous inorganic materials of the presentinvention would be suitable for a variety of applications. FIG. 3depicts a discoidal filter scaffold 16, which is prepared in accordancewith the present invention, and enclosed within an exterior filterhousing 18 for filtration or bioseparation applications. Depending uponits end use, discoidal filter scaffold 16 can be a biologically active,impregnated porous scaffold Arrow 20 represents the inlet flow stream.Arrow 22 represents the process outlet stream after passing throughdiscoidal filter scaffold 16.

FIG. 4 illustrates a block of the porous inorganic material that is usedas a catalyst support within a two stage, three way hot gas reactor ordiffusor. Items 30 and 32 illustrate blocks of the porous material usedas catalytically impregnated scaffolds. Items 30 and 32 may be composedof the same or different material. Both 30 and 32, however, are preparedin accordance with an embodiment of the present invention. Item 34depicts the first stage catalyst housing, which may be comprised of aferrous-containing material, and encloses item 30. Item 36 depicts thesecond stage catalyst housing, which may be comprised of aferrous-containing material, and encloses item 32. Item 38 representsthe connector pipe, which is comprised of the same material as thehousings 34 and 36, and connects both 34 and 36. Arrow 40 represents theraw gas inlet stream prior to passing through both blocks ofcatalytically impregnated scaffold (items 30 and 32). Arrow 42, lastly,represents the processed exhaust gas stream.

In other embodiments of the present invention, the inorganic porousmaterial is a calcium phosphate scaffolding material that may beemployed for a variety of uses. FIG. 5 illustrates a block of thecalcium phosphate scaffolding material 55 that may be inserted into ahuman femur and used for cell seeding, drug delivery, proteinadsorption, growth factor introduction or other biomedical applications.Femoral bone 51 is comprised of metaphysis 52, Haversian canal 53,diaphysis 54 and cortical bone 56. The calcium phosphate scaffoldingmaterial 55 is inserted into an excavation of the femoral bone as shownand ties into the Haversian canal allowing cell seeding, drug delivery,or other applications. Scaffolding material 55 can be used in the samemanner in a variety of human or mammalian bones.

FIG. 6A shows the calcium phosphate material of the present inventionformed into the shape of a calcium phosphate sleeve 60. Item 62 depictsthe excavated cavity which can be formed via machining or other means.Item 64 presents a plurality of threads which can be coated withbioactive bone cement. FIG. 6B shows the calcium phosphate sleeve 60inserted into the jaw bone 66 and gum 67. The calcium phosphate sleeve60 may be fixed in place via pins, bone cement, or other mechanicalmeans of adhesion. An artificial tooth or dental implant 68 can then bescrewed into sleeve 60 by engaging threads 64.

FIG. 7A shows the porous, calcium phosphate scaffolding material 70,prepared in accordance with an embodiment of the present invention,which is machined or molded to patient specific dimensions. FIG. 7Bdepicts the use of the material 70 that is formed into the shape ofcraniomaxillofacial implant 76, a zygomatic reconstruction 72, or amandibular implant 74.

FIG. 8A depicts a plug of the porous, calcium phosphate scaffoldingmaterial 80. FIG. 8B illustrates plug 80 which is inserted into anexcavation site 83 within a human knee, below the femur 81 and above thetibia 82, for use in a tibial plateau reconstruction. Plug 80 is held inplace or stabilized via a bone cement layer 84.

FIG. 9 shows the calcium phosphate scaffolding material within a humanfemur that is used as a block 92 for bulk restoration or repair of bulkdefects in metaphyseal bone or oncology defects, or as a sleeve 94 foran orthopaedic screw, rod or pin 98 augmentation. Item 99 depicts anorthopaedic plate anchored by the orthopaedic device item 98. Bonecement layer 96 surrounds and supports sleeve 94 in place.

Lastly, FIGS. 10A and 10B depict the use of the calcium phosphatescaffolding material as a receptacle sleeve 100 that is inserted intothe body to facilitate a bipolar hip replacement. Alternatively, thereceptacle sleeve may be comprised of other materials known in the art.Cavity 102 is machined to accommodate the insertion of a metallic balljoint implant or prosthesis 103. An orthopaedic surgeon drills a cavityor furrow into the bone 101 to receive sleeve 100. Sleeve 100 is thenaffixed to the surrounding bone via a bioactive or biocompatible bonecement layer 104 or other means. On the acetabular side, a femoral headarticulation surface 106 is cemented to a bone cement layer 104 thatresides within a prepared cavity with material of the present invention,100. A high molecular weight polyethylene cup, 105 is used to facilitatearticulation with the head of the prosthesis 103. The metallic balljoint implant or prosthesis 103 is thus inserted into a high molecularweight polyethylene cup 105 to facilitate joint movement.

Orthopaedic appliances such as joints, rods, pins, sleeves or screws fororthopaedic surgery, plates, sheets, and a number of other shapes may beformed from the calcium phosphate scaffolding material in and of itselfor used in conjunction with conventional appliances that are known inthe art. Such porous inorganic bodies can be bioactive and can be used,preferably, in conjunction with biocompatible gels, pastes, cements orfluids and surgical techniques that are known in the art. Thus, a screwor pin can be inserted into a broken bone in the same way that metalscrews and pins are currently inserted, using conventional bone cementsor restoratives in accordance with the present invention or otherwise.The bioactivity of the calcium phosphate scaffolding material will giverise to osteogenesis with beneficial medical or surgical results. Forexample, calcium phosphate particles and/or shaped bodies prepared inaccordance with this invention can be used in any of the orthopaedic ordental procedures known for the use of calcium phosphate; the proceduresof bone filling defect repair, oncological defect filling,craniomaxillofacial void filling and reconstruction, dental extractionsite filling, and potential drug delivery applications.

The scaffold structures of this invention, calcium phosphate inparticular, can be imbibed with blood, cells (e.g. fibroblasts,mesenchymal, stromal, marrow and stem cells), protein rich plasma otherbiological fluids and any combination of the above. Experiments havebeen conducted with ovine and canine blood (37° C.) showing the abilityof the scaffold to maintain its integrity while absorbing the blood intoits pores. This capability has utility in cell-seeding, drug delivery,and delivery of biologic molecules as well as in the application of bonetissue engineering, orthopaedics, and carriers of pharmaceuticals. Thismakes the Ca-P scaffold ideal for the use as an autograft extender orreplacement graft material.

The scaffold structures, especially calcium phosphate, can be imbibedwith any bioabsorbable polymer or film-forming agent such aspolycaprolactones (PCL), polyglycolic acid (PGA), poly-L-Lactic acid(PL-LA), polysulfones, polyolefins, polyvinyl alcohol (PVA),polyalkenoics, polyacrylic acids (PAA), polyesters and the like.Experiments have been conducted with PCL, by solubilizing the PCL in anevaporative solvent and saturating a plug of calcium phosphate scaffoldstructure, allowing the structure to dry, and thus fixing the PCL ontothe surface and throughout the body of the scaffold. The resultant massis strong, carveable, and somewhat compressible. Experiments showed thatthe PCL coated material still absorbs blood. Numerous other uses forthese minerals and shaped bodies comprised thereof are anticipated. Theoxidizing agents, reducing agents, ratios, co-reactants and otheradducts, products and exemplary uses will be understood by inorganicchemists from a review of the aforementioned chemical reactions. Calciumphosphates are indicated for biological restorations, dentalrestorations, bioseparations media, and ion or protein chromatography.Transition metal phosphates (Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn)and shaped, porous articles thereof have numerous potential uses aspigments, phosphors, catalysts, electromagnetic couplers, microwavecouplers, inductive elements, zeolites, glasses, nuclear wastecontainment systems, radomes and coatings. Addition of rare-earthsphosphates can lead to uses as intercalation compounds, catalysts,catalyst support material, glasses and ceramics, radiopharmaceuticals,pigments and phosphors, medical imaging agents, nuclear wastesolidification, electro-optics, electronic ceramics, and surfacemodifications.

Aluminum and zirconium phosphates and shaped, porous articles thereofare ideal candidates for surface protective coatings, abrasiveparticles, polishing agents, cements, and filtration products in eithergranular form or as coatings. The alkali (Na, K, Rb, Cs) andalkaline-earth (Be, Mg, Ca, Sr, Ba) phosphates and shaped, porousarticles thereof would generate ideal low temperature glasses, ceramics,biomaterials, cements, glass to metal seals, and other numerousglass-ceramic materials, such as porcelains, dental glasses,electro-optic glasses, laser glasses, specific refractive index glassesand optical filters. It is to be understood that the diverse chemistriesset forth herein may be applied to the creation of shaped bodies of theinvention.

It will be appreciated that, in accordance with certain embodiments ofthis invention, RPR-derived materials will be caused to exist on or in afirst solid portion of material. The resulting composite structuresoffer highly desirable properties and are useful for a very wide rangeof applications. The RPR-derived portions of the composite shaped bodiesof the invention form one portion of those bodies. The other portion ofthe shaped bodies is comprised of another, solid material. The materialswhich can make up the non-RPR-derived portion or portions of the shapedbodies can be any of a wide variety of compositions which are consistentwith the overall objects of this invention. Thus, such materials may bemetal, such as stainless steel, titanium, amalgam, silver, gold and thelike. Metals stable to the human body are preferred although fornon-surgical uses others can be employed as well. These materials may beceramic or glass. In this context, bioactive glasses and ceramics arepreferred. 45S5 glass materials are osteostimulatory and osteogeneticand can be used profitably in certain restorations. Many ceramics arebiostable, strong and well suited to use in this invention. Plasticmaterials may be the most flexible, however and will be preferred inmany applications. In any event, any solid material can form thenon-RPR-derived portion or portions of the shaped bodies of theinvention so long as they are stable to the intended use and to theRPR-derived material and can be formed or adhered therewith.

Of the polymers, the acrylics are preferred. Chief among this class foruse with the present invention are acrylic polymers including inorganicfillers. Any of this class, which is known per se, may be used. Thepreferred material is known as Orthocomp™ sold by Orthovita Corporationof Malvern, Pa. Orthocomp™ is an acrylic having inorganic filler. Aspart of the inorganic filler, the mineral Combeite is included. Thisfiller system has been found to be biostable and bioactive. U.S. Pat.Nos. 5,681,872 and 5,914,356, assigned to the assignee of thisinvention, are directed to materials of this class and are incorporatedherein by reference as if set forth in full. These polymers are easilyworked with, are hard, strong and bioactive.

It will be appreciated that during formation, RPR-derived materials may,indeed, be formed in conjunction with another solid material, e.g.sponge, glass or metal surfaces and the like. In general, the RPRmaterial is removed from such solid material prior to furtheremployment. Thus, the sponge can be pyrolyzed, the RPR material removedfrom metal or glass plates after formation and the like. The solidmaterials used in this fashion are used to facilitate formation of theRPR material. While, in some cases, direct formation of RPR material incontact with a solid portion of dissimilar material may be performed inconnection with this invention, solid materials, such as spongiformmaterials, used solely for formation of RPR, which materials are removedprior to final fabrication or use, are not the kind of solid materialscontemplated hereby. Thus, the solid materials upon which theRPR-derived materials are to be found exclude solid materials which aremerely transitory.

The composite shaped bodies of the invention may be prepared in anyconvenient way. Thus a shape of RPR-derived material may be sprayed,dipped, brushed or otherwise coated with a polymerizable material,especially the Orthocomp™ material, and the same caused to polymerize.Alternatively, the RPR material may be formed around a core or layer ofother material such a polymer, metal, etc. A further option is for apolymeric, metallic ceramic or other shape to be prepared and filledwith RPR-derived material. Since the RPR-derived material does notrequire the application of high temperatures, this procedure is easilyapplicable to a host of embodiments.

Complex structures can be made. Thus, shaped bodies having three, fourand more portions are useful for some embodiments of the invention. Forexample, a metal strut may be surrounded by RPR-derived calciumphosphate and the whole coated with Orthocomp™ or other polymer. Theresulting shaped body may be used in orthopaedic and other applications.Sandwich constructs like the “crouton” showed in FIG. 45 are also easilyprepared. Persons of skill in the art will have no difficulty inpreparing shaped bodies with the composite nature of the presentinvention.

Exemplary composite shaped bodies are shown in the drawings. FIG. 29depicts a pair of vertebrae 200 in a spine having a synthetic corticalring 202 inserted therebetween. The vertebral ring has one or moreaccess ports 204 present an in communication with the interior of thering. Injection of hardenable material via a syringe device 206 can beaccomplished via the port or ports. The hardenable material may beorganic, inorganic or mixed and is generally a bone cement or polymericbonding material.

FIG. 30 is a lateral view of a synthetic cortico-cancellous vertebralring or interbody fusion device 202. In this embodiment, the ring iscomposite, having a first portion 210 comprised of a first material anda second portion 212 comprised of a second material. The material of theinternal portion 212 is preferably RPR derived porous, inorganic calciumphosphate. FIG. 31 shows one embodiment of a synthetic cortical bonedowel in place. The dowel has a plurality of ports, some of which areshown 224. Hardenable material such as bone cement is injected into thedowel, emerging from the ports to form a partial surround of the dowel228. FIG. 32 depicts another bone dowel for spinal fusion. The end of aninjection device or syringe 226 is shown. Bone cement 224 is shown aswell emerging from access ports 228 in the dowel.

FIG. 33 shows a synthetic cortical interbody vertebral defect fillingform. It, too may be employed with bone cement or otherwise. FIG. 34 isa cross sectional view of a bone dowel in place to accomplish spinalfusion. The dowel itself, 222, is shown potted within hardenablematerial 228 injected around and/or through the dowel.

FIGS. 35 a through c depict synthetic cortical vertebral spacers orinterbody devices. Hard material, 240 preferably composite material inaccordance with the invention, forms the spacers and rings. In preferredembodiments a plurality of regions form a composite shaped body asillustrated in FIG. 35 c. Hard material such as filled acrylic polymer240 forms an outer portion of the ring, while porous RPR-derivedmaterial, especially a calcium phosphate 242 forms an inner portion ofthe body.

FIGS. 36 a through c depict synthetic cortical bone dowels or interbodydevices 250. The dowels may have access ports 252 for emergence ofhardenable material when such material is injected into orifice 254 witha syringe device. The dowels and devices may be composite as set forthherein. FIG. 37 is another form of cortical spacer. The spacer has arelatively hard outer portion 260 and RPR derived inner portion 262.FIG. 38 is of a synthetic cancellous bone dowel. The dowel as depictedpreferably has a heterogenous core material such as a hard plastic,ceramic or metal.

The intervertebral body implants of FIGS. 30-34 and 35 a-36 c may beused in conjunction with a sleeve. The sleeve may surround the constructto prevent leakage of the bone cement or calcium phosphate materialplaced within the construct.

The sleeve may be used alone or in conjunction with an outer dowel orring to contain the material. If used alone, the sleeve forms the outerportion of the construct and the bone cement or calcium phosphate formsthe inner portion of the construct. The sleeve may be comprised of avariety of materials known in the art including metals, polymers orceramics, and may be resorbable or non-resorbable.

FIG. 39 is a synthetic cortical vertebral interbody device of anotherform. An inner portion is formed of RPR derived calcium phosphate. FIGS.40 a and c are of synthetic cortico-cancellous defect filling forms forbone restoration. Hard portion 270 is combined with an RPR-derivedcalcium phosphate portion 272 to give rise to these composite shapedbodies. FIG. 40 b is a cancellous defect filling form for restoration.It is preferably formed from RPR-derived calcium phosphate 272 andpreferably has a metallic, polymeric or ceramic underlayment of support,not shown. FIG. 41 a is drawn to a cortico-cancellous bone dowel 280.Roughened area 282 is preferably derived from RPR material. A port foraccess to the interior of the dowel 286 is provided. The Dowelpreferably has heterogeneous support portions in the interior.

FIG. 41 b is another bone dowel 280 in different conformation. Injectionport 286 communicate with the interior. Orifice 284 and other structurefacilitates spread of bone cement.

FIG. 42 is a synthetic cortical ring. Hard outer ring structure mayeither surround a void 292 or the void may be filled, e.g. withRPR-derived calcium phosphate material. The ring may also have innerportion formed from a heterogeneous material.

FIG. 43 is a cortical rod for orthopaedic restoration. FIG. 44 is asynthetic cortico-cancellous “tri-cortical” device for orthopaedicreconstructive surgery. Hard, preferably polymeric outer portionsubstantially 300 surrounds a porous inner structure 302, preferablyderived from RPR calcium phosphate. FIG. 45 depicts a cortico-cancellous“crouton” for orthopaedic surgery. Polymeric shell, preferably oneformed from bioactive polymer, 300, overlays a layer of RPR-derivedcalcium phosphate to form this composite shaped body. FIG. 46 is a“match stick” orthopaedic surgical splint. FIGS. 47 a and 47 b arecortical struts. They are preferably comprised of a plurality ofportions, one of which is an RPR-derived calcium phosphate.

FIGS. 48 and 49 show cortical rings having bioactive polymeric outerportion 310 and RPR-derived calcium phosphate inner portion 312. FIGS.50 a and 50 b are cortical rings. These preferably have heterogenousinner support or reinforcement portions. FIG. 51 depicts an artificialfemur head for reconstructive surgery. Outer portion 320 is preferablyformed from hardened polymer while an inner portion 322 is RPR-derivedcalcium phosphate. This structure mimics natural bone

FIG. 52 is an artificial bone portion having hard outer portion andRPR-derived calcium phosphate inner portion. FIG. 53 is a strut or tubeshowing RPR-derived inner portion 322 surrounded by hardened polymer320. FIG. 54 is an acetabular/pelvic form for orthopaedicreconstruction. The inner RPR structure 322 and outer polymeric portions320 are shown.

FIGS. 55 a and b depict insertion of a femoral hip dowel 330 into afemur, shown in phantom, requiring restoration. Access ports 332 permitthe injection of hardenable material, such as bone cement, into thedowel and, via the ports, around the dowefto effect fixation in thefemur head. FIGS. 56 a through d are different forms of dowels 330 ofthe type useful for hip or other reconstruction. Optional access ports332 are present in FIGS. 56 b and 56 d.

EXAMPLES Example 1 Low Temperature Calcium Phosphate Powders

An aqueous solution of 8.51 g 50 wt % hypophosphorous acid, H₃PO₂(Alfa/Aesar reagent #14142, CAS #6303-21-5), equivalent to 71.95 wt %[PO₄]⁻³ was combined with 8.00 g distilled water to form a clear,colorless solution contained in a 250 ml Pyrex beaker. To this solutionwas added 22.85 g calcium nitrate tetrahydrate salt, Ca(NO₃)₂.4H₂O (ACSreagent, Aldrich Chemical Co., Inc. #23,712-4, CAS #13477-34-4),equivalent to 16.97 wt % Ca. The molar ratio of Ca/phosphate in thismixture was 3/2 and the equivalent solids level [as Ca₃(PO₄)₂] was 25.4wt %. Endothermic dissolution of the calcium nitrate tetrahydrateproceeded under ambient temperature conditions, eventually forming ahomogeneous solution. Warming of this solution above 25° C. initiated areaction in which the solution vigorously bubbled while evolvingred-brown acrid fumes characteristic of NO_(x(g)). The sample turnedinto a white, pasty mass which foamed and pulsed with periodic expulsionof NO_(x(g)). After approximately two minutes, the reaction wasessentially complete, leaving a white, pasty mass which was warm to thetouch. After cooling to room temperature, the solid (A) was stored in apolyethylene vial.

Three days after its preparation, a few grams of the damp, pasty solidwere immersed in 30 ml distilled water in order to “wash out” anyunreacted, water soluble components. The solid was masticated with aspatula in order to maximize solid exposure to the water. Afterapproximately 15 minutes, the solid was recovered on filter paper andthe damp solid (B) stored in a polyethylene vial.

X-ray diffraction (XRD) patterns were obtained from packed powdersamples using the Cu—Kα line (λ=1.7889 Angstrom) from a RigakuGeigerflex instrument (Rigaku/USA, Inc., Danvers, Mass. 01923) run at 45kV/30 mA using a 2 degree/minute scan rate over the 2θ angular rangefrom 15-50° or broader. Samples were run either as prepared or followingheat treatment in air in either a Thermolyne type 47900 or a Ney model3-550 laboratory furnace. XRD analysis of the samples yielded thefollowing results: Heat Major Minor Sample treatment phase phaseUnwashed (A) As prepared Undetermined — Unwashed (A) 300° C., 1 hourMonetite [CaHPO₄] — Unwashed (A) 500° C., 1 hour Whitlockite CaH₂P₂O₇[β-Ca₃(PO₄)₂] Unwashed (A) 700° C., 1 hour Whitlockite [β-Ca₃(PO₄)₂] +HAp[Ca₅(PO₄)₃(OH)] Washed (B) As prepared Monetite [CaHPO₄] Washed (B)100° C., 1 hour Monetite [CaHPO₄]

Additional amounts of NO_(x(g)) were evolved during firing of thesamples at or above 300° C.

A sample of the powder produced according to this Example was submittedto an outside laboratory for analysis (Corning, Inc., CELS-LaboratoryServices, Corning, N.Y. 14831). The results of this outside lab analysisconfirmed that the powder fired at 700° C. was comprised of whitlockiteand hydroxyapatite.

Example 2 Low Temperature Calcium Phosphate Powder

Example 1 was repeated using five times the indicated weights ofreagents. The reactants were contained in a 5½″ diameter Pyrexcrystallizing dish on a hotplate with no agitation. Warming of thehomogeneous reactant solution above 25° C. initiated an exothermicreaction which evolved red-brown acrid fumes characteristic ofNO_(x(g)). Within a few seconds following onset of the reaction, thesample turned into a white, pasty mass which continued to expelNO_(x(g)) for several minutes. After approximately five minutes, thereaction was essentially complete leaving a damp solid mass which washot to the touch. This solid was cooled to room temperature underambient conditions for approximately 20 minutes and divided into twoportions prior to heat treatment.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air, XRD indicatedthe fired solids to be composed of: Heat Major Minor Sample treatmentphase phase A 500° C., 1 hour Whitlockite HAp [β-Ca₃(PO₄)₂][Ca₅(PO₄)₃(OH)] B 700° C., 1 hour HAp Whitlockite [Ca₅(PO₄)₃(OH)][β-Ca₃(PO₄)₂]

Example 3 Low Temperature Calcium Phosphate Powders

An aqueous solution of 8.51 g 50 wt % H₃PO₂ was combined with 8.00 g of25.0 wt % aqueous solution of calcium acetate monohydrate,Ca(O₂CCH₃)₂.H₂O (ACS reagent, Aldrich Chemical Co., Inc. #40,285-0, CAS5743-26-0), equivalent to 5.69 wt % Ca, to give a clear, colorlesssolution contained in a 250 ml Pyrex beaker. To this solution was added20.17 g Ca(NO₃)₂4.H₂O salt. The molar ratio of Ca/phosphate in thismixture was 3/2 and the equivalent solids level [as Ca₃(PO₄)₂] was 27.3wt %. Endothermic dissolution of the calcium nitrate tetrahydrate saltproceeded giving a homogeneous solution once the sample warmed to roomtemperature. Further warming of this solution to >25° C. on a hotplateinitiated a reaction which proceeded as described in Example 1. Afterapproximately three minutes, the reaction was essentially completeleaving a moist, white, crumbly solid which was hot to the touch andwhich smelled of acetic acid. After cooling to room temperature, thesolid was stored in a polyethylene vial.

Heat treatment and X-ray diffraction analysis of this solid wereconducted as described in Example 1. Following heat treatment in air at500° C. for either 0.5 or 1 hour, XRD indicated the solid to be composedof whitlockite as the primary phase along with hydroxyapatite as thesecondary phase. XRD results indicate that the relative ratio of the twocalcium phosphate phases was dependent on the duration of the heattreatment and the presence of the acetate anion, but no attempts weremade to quantify the dependence. $\begin{matrix}{{{Heated}\quad{to}\quad 500^{{^\circ}}\quad{C.}},{1\quad{hour}\quad({Major})}} & {{Whitlockite}\quad\left\lbrack {\beta - {{Ca}_{3}\left( {PO}_{4} \right)}_{2}} \right\rbrack} \\{\quad({minor})} & {{{{Ca}_{5}\left( {PO}_{4} \right)}_{3 - x}\left( {CO}_{3} \right)_{x}({OH})}\quad}\end{matrix}$

Comparing the XRD spectra from these results in Example 3 with XRDspectra from Example 1 shows the difference in the amount ofHAp-Ca₅(PO₄)_(3-x)(CO₃)_(x)(OH) phase present for each minor phase. Thesamples in Example 1 exhibited no acetate whereas the samples in Example3 showed acetate present. This is indicative of the counteranion effecton crystal formation.

Fourier Transform Infrared (FTIR) spectra were obtained using a Nicoletmodel 5DXC instrument (Nicolet Instrument Co., 5225 Verona Rd. Madison,Wis. 53744) run in the diffuse reflectance mode over the range of 400 to4000 cm⁻¹. The presence of the carbonated form of HAp is confirmed bythe FTIR spectra, which indicated the presence of peaks characteristicof [PO₄]⁻³ (580-600, 950-1250 cm⁻¹) and of [CO₃]⁻² (880, 1400, & 1450cm⁻¹). The P═O stretch, indicated by the strong peak at 1150-1250 cm⁻¹,suggests a structural perturbation of hydroxyapatite by the carbonateion.

Example 4 Colloidal SiO₂ Added to Calcium Phosphate Mixtures Via RPR

An aliquot of 8.00 g 34.0 wt % SiO₂ hydrosol (Nalco Chemical Co., Inc.#1034A, batch #B5G453C) was slowly added to 8.51 g 50 wt % aqueoussolution of H₃PO₂ with rapid stirring to give a homogeneous, weaklyturbid colloidal dispersion. To this dispersion was added 22.85 gCa(NO₃)₂4.H₂O salt such that the molar ratio of calcium/phosphate in themixture was 3/2. Endothermic dissolution of the calcium nitratetetrahydrate proceeded giving a homogeneous colloidal dispersion oncethe sample warmed to room temperature. The colloidal SiO₂ was notflocculated despite the high acidity and ionic strength in the sample.Warming of the sample on a hotplate to >25° C. initiated a reaction asdescribed in Example 1. The resultant white, pasty solid was stored in apolyethylene vial.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. for1.0 hour, XRD indicated the solid to be composed of whitlockite plushydroxyapatite. $\begin{matrix}{{{{Heated}\quad{to}\quad 300^{{^\circ}}\quad{C.}},{2\quad{hours}\quad({Major})\quad{Calcium}\quad{{pyrophosphate}\quad\left\lbrack {{Ca}_{2}P_{2}O_{7}} \right\rbrack}}}\quad} \\{\quad{({minor})\quad{Octacalium}\quad{phosphate}}\quad}\end{matrix}\left\lbrack {{Ca}_{4}{{H\left( {PO}_{4} \right)}_{3} \cdot 2}\quad H_{2}O} \right\rbrack$Heated  to  500^(^(∘))  C., 1  hour  (Major)  Whitlockite  [b − Ca₃(PO₄)₂]  (minor)  HAp  [Ca₅(PO₄)₃(OH)]  

Example 5 Low Temperature Calcium Phosphate Powder

Example 1 was repeated with the addition of 10.00 g dicalcium phosphatedihydrate, DCPD, CaHPO_(4.2)H₂O (Aldrich Chemical Co., Inc. #30,765-3,CAS #7789-77-7) to the homogeneous solution following endothermicdissolution of the calcium nitrate salt. The DCPD was present both assuspended solids and as precipitated material (no agitation used).Warming of the sample to >25° C. initiated an exothermic reaction asdescribed in Example 1, resulting in the formation of a white, pastysolid. Heat treatment and X-ray diffraction of this solid were conductedas described in Example 1. Following heat treatment in air at 500° C.for 1 hour, XRD indicated the solid to be composed of whitlockite as theprimary phase along with calcium pyrophosphate (Ca₂P₂O₇) as thesecondary phase. $\begin{matrix}{{{{Heated}\quad{to}\quad 500^{{^\circ}}\quad{C.}},{1\quad{hour}}}\quad} & ({Major}) & {{Whitlockite}\quad\left\lbrack {\beta - {{Ca}_{3}\left( {PO}_{4} \right)}_{2}} \right\rbrack} \\\quad & ({minor}) & {{Ca}_{2}P_{2}O_{7}}\end{matrix}$

Example 6 Low Temperature Zinc Phosphate Powder Preparation

An aqueous solution of 8.51 g 50 wt % H₃PO₂ in 8.00 g distilled waterwas prepared as described in Example 1. To this solution was added 28.78g zinc nitrate hexahydrate salt, Zn(NO₃)₂.6H₂O (ACS reagent, AldrichChemical Co., Inc. #22,873-7, CAS # 10196-18-6), equivalent to 21.97 wt% Zn. The molar ratio of Zn/phosphate in this mixture was 3/2 and theequivalent solids level [as Zn₃(PO₄)₂] was 27.5 wt %. Endothermicdissolution of the zinc nitrate hexahydrate proceeded giving ahomogeneous solution once the sample warmed to room temperature. Furtherwarming of this solution to >25° C. on a hotplate initiated a reactionin which the solution vigorously evolved red-brown acrid fumes ofNO_(x(g)). The reaction continued for approximately 10 minutes while thesample remained a clear, colorless solution, abated somewhat for aperiod of five minutes, then vigorously resumed finally resulting in theformation of a mass of moist white solid, some of which was veryadherent to the walls of the Pyrex beaker used as a reaction vessel. Thehot solid was allowed to cool to room temperature and was stored in apolyethylene vial.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. for 1hour, XRD indicated the solid to be composed of Zn₃(PO₄)₂ (PDF 30-1490).Heated to 500° C., 1 hour (Major) Zn₃(PO₄)₂

Example 7 Low Temperature Iron Phosphate Powders

An aqueous solution of 17.50 g 50 wt % H₃PO₂ was combined with 15.00 gdistilled water to form a clear, colorless solution contained in a 250ml Pyrex beaker on a hotplate/stirrer. To this solution was added 53.59g ferric nitrate nonahydrate salt, Fe(NO₃)₃-9H₂O (ACS reagent,Alfa/Aesar reagent #33315, CAS #7782-61-8), equivalent to 13.82 wt % Fe.The molar ratio of Fe/phosphate in this mixture was 1/1 and theequivalent solids level [as FePO₄] was 23.2 wt %. Endothermicdissolution of the ferric nitrate nonahydrate salt proceeded partiallywith gradual warming of the reaction mixture, eventually forming a palelavender solution plus undissolved salt. At some temperature >25° C., anexothermic reaction was initiated which evolved NO_(x(g)). This reactioncontinued for approximately 15 minutes during which time the reactionmixture became syrup-like in viscosity. With continued reaction, somepale yellow solid began to form at the bottom of the beaker. Afterapproximately 40 minutes of reaction, the sample was allowed to cool toroom temperature. The product consisted of an inhomogeneous mixture oflow density yellow solid at the top of the beaker, a brown liquid withthe consistency of caramel at the center of the product mass, and a sandcolored solid at the bottom of the beaker. The solids were collected asseparate samples insofar as was possible.

Heat treatment and X-ray diffraction of the solid collected from the topof the beaker were conducted as described in Example 1. Following heattreatment in air at 500° C. for 1 hour, XRD indicated the solid to becomposed of graftonite [Fe₃(PO₄)₂] (PDF 27-0250) plus some amorphousmaterial, suggesting that the heat treatment was not sufficient toinduce complete sample crystallization as illustrated below:Heated to 500° C., 1 hour (Major) Graftonite [Fe₃(PO₄)₂]Some mechanism apparently occurs by which Fe was reduced to Fe²⁺.

Example 8 Low Temperature Calcium Phosphate Powders

An aqueous solution of 19.41 g 50 wt % H₃PO₂ was combined with 5.00 gdistilled water to form a clear, colorless solution contained in a 250ml Pyrex beaker. To this solution was added 34.72 g Ca(NO₃)₂.4H₂O. Themolar ratio of Ca/phosphate in this mixture was 1/1 and the equivalentsolids level [as CaHPO₄] was 33.8 wt %. Endothermic dissolution of thecalcium nitrate tetrahydrate proceeded under ambient temperatureconditions, eventually forming a homogeneous solution once the samplewarmed to room temperature. Warming of this solution above 25° C.initiated a vigorous exothermic reaction which resulted in the evolutionof NO_(x(g)), rapid temperature increase of the sample to >100° C., andextensive foaming of the reaction mixture over the beaker rim,presumably due to flash boiling of water at the high reactiontemperature. After cooling to room temperature, the reaction product wascollected as a dry, white foam which was consolidated by crushing to apowder.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Results are as follows: $\begin{matrix}{{{{Heated}\quad{to}\quad 300^{{^\circ}}\quad{C.}},{2\quad{hours}}}\quad} & ({Major}) & {{{Ca}_{2}P_{2}O_{7}}\quad} \\\quad & ({minor}) & {{Octacalcium}\quad{phosphate}}\end{matrix}$ $\begin{matrix}{\left\lbrack {{{Ca}_{4}{H\left( {PO}_{4} \right)}_{3}} - {2\quad H_{2}O}} \right\rbrack\quad} \\{{{Heated}\quad{to}\quad 500^{{^\circ}}\quad{C.}},{1\quad{hour}\quad({Major})\quad{Ca}_{2}P_{2}O_{7}}}\end{matrix}$

Example 9 Low Temperature Calcium Phosphate Powders

Example 3 was repeated using ten times the indicated weights ofreagents. The reactants were contained in a 5½″ diameter Pyrexcrystallizing dish on a hotplate/stirrer. The reactants were stirredcontinuously during the dissolution and reaction stages. The chemicalreaction initiated by heating the solution to >25° C. resulted in theevolution of NO_(x(g)) for several minutes with no apparent effect onthe stability of the system, i.e. the solution remained clear andcolorless with no evidence of solid formation. After abating for severalminutes, the reaction resumed with increased intensity resulting in thevoluminous generation of NO_(x(g)) and the rapid appearance of a pastywhite solid material. The reaction vessel and product were both hot fromthe reaction exotherm. The product was cooled in air to a white crumblysolid which was stored in a polyethylene vial.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. foreither 0.5 or 1 hour, XRD indicated the solid to be composed ofwhitlockite as the primary phase along with hydroxyapatite as thesecondary phase. XRD results indicate that the relative ratio of the twocalcium phosphate phases was dependent on the duration of the heattreatment, but no attempts were made to quantify the dependence.Heated  to  500^(^(∘))  C., 1  hour  (Major)  Whitlockite  [b − Ca₃(PO₄)₂]  (minor)  Ca₅(PO₄)_(3 − x)(OH)  

Example 10 Low Temperature Aluminum Phosphate Powders

An aqueous solution of 10.82 g 50 wt % H₃PO₂ was combined with 2.00 gdistilled water to form a clear, colorless solution contained in a 250ml Pyrex beaker. To this solution was added 30.78 g aluminum nitratenonahydrate salt, Al(NO₃)₃.9H₂O (ACS reagent, Alfa/Aesar reagent #36291,CAS #7784-27-2), equivalent to 7.19 wt % Al. The molar ratio ofAl/phosphate in this mixture was 1/1 and the equivalent solids level [asAlPO₄] was 22.9 wt %. Endothermic dissolution of the aluminum nitratenonahydrate proceeded giving a homogeneous solution once the samplewarmed to room temperature. Further warming of this solution to >25° C.on a hotplate initiated a reaction in which the solution vigorouslyevolved red-brown acrid fumes of NO_(x(g)). Reaction continued forapproximately 15 minutes during which the solution viscosity increasedconsiderably prior to formation of a white solid.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. for0.5 hour, XRD analysis indicated the solid to be composed of AlPO₄ (PDF11-0500) plus some amorphous material, suggesting that the heattreatment was not sufficient to induce complete sample crystallization.

Example 11 Low Temperature Calcium Phosphate Powders

An aqueous solution of 8.06 g 50 wt % H₃PO₂ reagent was combined with6.00 g distilled water to form a clear, colorless solution in a 250 mlPyrex beaker on a hotplate/stirrer. To this solution was added 19.23 gCa(NO₃)₂.4H₂O. The molar ratio of Ca/phosphate in this sample was 4/3and the equivalent solids [as octacalcium phosphate, Ca₈H₂(PO₄)₆6-5H₂O]was 30.0 wt %. Endothermic dissolution of the calcium nitratetetrahydrate proceeded under ambient conditions, eventually forming ahomogeneous solution once the sample warmed to room temperature. Warmingof the solution above 25° C. initiated a vigorous exothermic reaction asdescribed in Example 1. After approximately three minutes, the reactionwas essentially complete leaving a moist, white, pasty solid.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. for0.5 hour, XRD indicated the solid to be composed of whitlockite as theprimary phase along with hydroxyapatite as the secondary phase. Therewas no evidence for the formation of octacalcium phosphate (OCP),despite the initial sample stoichiometry. This result suggests that (a)alternate heat treatments are necessary to crystallize OCP and/or (b)excess Ca is present in the intermediate powder.Heated  to  500^(^(∘))  C., 0.5  hour  (Major)  Whitlockite  [b − Ca₃(PO₄)₂]  (minor)  HAp  Ca₅(PO₄)₃(OH)  

Example 12 Low Temperature Calcium Phosphate Powders

Example 11 was repeated except that no distilled water was used inpreparation of the reaction mixture. Warming of the homogeneous solutionabove 25° C. initiated an exothermic reaction as described in Example11. After approximately three minutes, the reaction was essentiallycomplete leaving a moist, pasty, white solid.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. for0.5 hour, XRD indicated the solid to be composed of calciumpyrophosphate (Ca₂P₂O₇).Heated to 500° C., 0.5 hour (Major) Ca₂P₂O₇

Example 13 Low Temperature Hydrothermal (HYPR) Calcium Phosphates

An aqueous solution of 50 wt % calcium nitrate tetrahydrate,Ca(NO₃)₂-4H₂O (ACS reagent, Aldrich Chemical Co., Inc. #23,712-4, CAS#13477-34-4) was prepared by dissolving 250.0 g of the salt in 250.0 gdistilled water. This solution was equivalent to 8.49 wt % Ca. A totalof 47.0 g of this solution was added, with rapid agitation, to anaqueous solution of 50 wt % sodium hypophosphite monohydrate,NaH₂PO₂—H₂O (Alfa/Aesar reagent #14104, CAS #10039-56-2) also preparedby dissolving 250.0 g of the salt in 250.0 g distilled water. The sodiumhypophosphite solution was equivalent to 44.80 wt % [PO₄]⁻³. The clear,colorless solution of calcium nitrate and sodium hypophosphite was thendiluted with 40.3 g distilled water. The molar ratio of Ca/phosphate inthis mixture was 5/3, and the equivalent solids level [as Ca₅(PO₄)₃(OH)(hydroxyapatite)] was 10.0 wt %. The sample was hydrothermally treatedusing a 300 cc volume stirred high pressure bench reactor (Model no.4561 Mini Reactor, Parr Instrument Co., Moline, Ill. 61265) equippedwith a temperature controller/digital tachometer unit (Model no. 4842,Parr Instrument Co.) and dial pressure gauge. All wetted parts of thereactor were fabricated from type 316 stainless steel. Ordinarily, type316SS is not the material of choice for inorganic acid systems such asthe solution precursors used in this invention, since phosphoric acidcan attack stainless steel at elevated temperatures and pressures.However, in the practice of this invention, direct contact (i.e.wetting) of the reactor surfaces was avoided through the use of a Pyrexglass liner. Only the stirrer and thermocouple sheath were immersed inthe reactant solutions and no corrosion was observed. In addition, it isassumed that the high nitrate ion concentration in the reactant mixtureprovided a passivating environment for the type 316SS.

One hundred grams (approximately 100 ml) of the calcium nitrate-sodiumhypophosphite solution was placed in the Pyrex liner of the reactor andthe intervening space between the glass liner and the reactor vessel wasfilled with distilled water to the level of the sample. This ensuredmaximum heat transfer to the sample since the reactor was externallyheated by an electric mantle. The approx. 100 ml sample volume leftsufficient head space in the reactor to accommodate solution expansionat elevated temperatures. The reactor was sealed by compression of aTeflon gasket. Heating of the reactor was performed at the maximum rateof the controller to a set point of 202° C. with constant stirring (500r.p.m.). The heating profile, as monitored by a thermocouple immersed inthe reactant mixture, was as follows: REACTOR THERMAL PROFILE Time (min)0 5 10 15 20 25 30 35 36 Temp. 22 49 103 122 145 155 179 197 200 (° C.)(hold) (+/−2° C.) Pressure — — — — — — 160 210 220 (psi)

After holding at 200+/−3° C. for 12 minutes, the temperature rapidlyincreased to 216° C. with a resultant increase in reactor pressure toapproximately 330 psi. This exothermic event quickly subsided asevidenced by the rapid drop in reactor temperature to 208° C. within twominutes as the Parr reactor approached thermal equilibrium via anear-adiabatic process. After 15 minutes at 200° C., the reactor wasremoved from the heating mantle, quenched in a cold water bath, andopened after the head space was vented to ambient pressure.

A white precipitate was present in the glass liner. The solid wascollected by vacuum filtration on a 0.45 micron membrane filter(Millipore, Inc., Bedford, Mass., 01730), washed several times withdistilled water, and dried at approximately 55° C. in a forcedconvection oven. X-ray diffraction of this solid was conducted asdescribed in Example 1.

X-Ray diffraction results indicate a unique, unidentifiable diffractionpattern.

Example 14 Low Temperature Hydrothermal (HYPR) Calcium Phosphate Powders

Example 13 was repeated except that 40.3 g of 1.0 M NaOH solution wasadded with rapid stirring to the homogeneous solution of calcium nitrateand sodium hypophosphite instead of the distilled water. This baseaddition resulted in the formation of a milk white dispersion,presumably due to precipitation of Ca(OH)₂.

The sample was hydrothermally processed as described in Example 13 withthe temperature set point at 207° C. The temperature ramp to 160° C. (25minutes) was as indicated for Example 13. At 30 minutes into the run, anexotherm occurred causing the temperature of the reaction mixture torise to a maximum of 221° C. within five minutes with a correspondingpressure increase to 370 psi. At 38 minutes into the experiment, thereactor was quenched to room temperature.

The reaction product consisted of a small amount of white precipitate.The material was collected as described in Example 13. X-ray diffractionof the dried sample was conducted as described in Example 1. XRD resultsindicated the solid to be comprised of the same unidentifiable pattern(crystal phase) found in Example 13 and minor amounts ofHAp-[Ca₅(PO₄)₃(OH)].

Example 15 Low Temperature Hydrothermal (HYPR) Calcium Phosphate Powders

A total of 47.0 g of a 50 wt % aqueous solution of calcium nitratetetrahydrate was diluted with 53.0 g distilled water. Then, 6.00 gcalcium hypophosphite salt, Ca(H₂PO₂)₂ (Alfa/Aesar reagent #56168, CAS#7789-79-9), equivalent to 23.57 wt % Ca and 111.7 wt % [PO₄]⁻³, wasslurried into the Ca(NO₃)₂ solution using rapid agitation. An unknownamount of the calcium hypophosphite remained undissolved in the roomtemperature sample. The solubility behavior of Ca(H₂PO₂)₂ in theCa(NO₃)₂ solution at elevated temperatures is unknown. The molar ratioof Ca/phosphate in this system was 1.91.

This sample was hydrothermally processed as described in Example 13 withthe temperature set point at 212° C. The temperature ramp to 200° C. wasas indicated for Example 13. At 39 minutes into the run, an exothermoccurred causing the temperature of the reaction mixture to rise to amaximum of 252° C. within three minutes with a corresponding pressureincrease to 640 psi. At 44 minutes into the experiment, the reactor wasquenched to room temperature.

The reaction product appeared as a voluminous white precipitate plussome suspended solids. The material was collected as described inExample 13. X-ray diffraction of the dried solid was conducted asdescribed in Example 1. XRD showed the major peak at position 30.2°(2-theta) which indicated the solid to be monetite, CaHPO₄. The uniquecrystal morphology is depicted in the scanning electron micrographrepresentation in FIG. 2.

Mixtures of the above described RPR and HYPR powders are useful in theformation of self-setting calcium phosphate cements for the repair ofdental and orthopaedic defects. The addition of specific components andsolubilizing liquids can also be added to form the precursor bonemineral constructs of this invention.

Example 16 Cement Compositions

Approximately 1.4 g of an alkaline solution (7 molar) formed using NaOHand distilled water, was mixed with 1.1 g of HYPR monetite [Example 15]and 1.1 g of RPR β-TCP-HAp(CO₃) [Example 3] in a glass mortar and pestlefor ˜45 seconds. After mixing, a smooth paste was formed, which wasscooped into a 3 ml polypropylene syringe and sealed for 20 minuteswithout being disturbed. Room temperature setting was observed after 20minutes, which was indicated by the use of a 454 gram Gilmore needle.The hardened cement analyzed by X-ray diffraction showed peaks whichrevealed a conversion to primarily type-B, carbonated apatite which isthe desired bone mineral precursor phase: $\begin{matrix}{{Cement}\quad{XRD}\quad{reveled}} & ({Major}) & {{{Ca}_{5}\left( {PO}_{4} \right)}_{3 - x}\left( {CO}_{3} \right)_{x}({OH})} \\\quad & ({minor}) & {{Whitlockite}\quad\left\lbrack {b - {{Ca}_{3}\left( {PO}_{4} \right)}_{2}} \right\rbrack}\end{matrix}$

Example 17 Cement Compositions

A stock solution was formed with the approximately 7 M NaOH solutionused in Example 1 and 1.0% polyacrylic acid (PAA). PAA is used as achelating setting additive and wetting agent. The above solution wasused with several powder combinations to form setting cements. A 50/50powder mix of HYPR monetite [Example 15] and RPR β-TCP-HAp(CO₃) [Example3], approximately 0.7 g, was mixed with a glass spatula on a glass platewith 0.39 g of the 1% PAA-NaOH solution (powder to liquid ratio=1.73).The cement was extruded through a 3 ml syringe and was set after beingleft undisturbed for 20 minutes at room temperature (23° C.).

Examples 18-34

Set Time Powder/ (min.) Powder/ Gilmore Needle Liquid ratio (454 grams)Example Powder Liquid (Consistency) # = (1200 grams) 18 HYPR monetite +RPR 7M NaOH 1/1/1.2 <20 min (#) (Ex. 1) 500° C. Alkaline Sol'n (slightlywet paste) 19 HYPR monetite 7M NaOH 1/1/1.2 <20 min (#) (Ex. 15) + RPRAlkaline Sol'n (wet paste) (Ex. 1) 700° C. 20 HYPR monetite 7M NaOH1/1/1 15-18 min (Ex. 15) + −50 μm Alkaline Sol'n (sl. wet paste)45S5^(#) glass 21 RPR (Ex. 1) 500° C. 7M NaOH 1.5/1 >40 min ‘neat’Alkaline Sol'n (wet paste) 22 RPR (Ex. 1) 300° C. + RPR 7M NaOH 1.7/1 40min (Ex. 9) Alkaline Sol'n (sl. wet paste) 500° C. 23 HYPR monetite 7MNaOH 1/1/1.4 No Set up to (Ex. 15) + Commercial Alkaline Sol'n(v.gritty,wet) 24 hrs. β- TCP 24 HYPR monetite 7M NaOH 1/1/1.4 20 min(#) (Ex. 15) + RPR Alkaline Sol'n (slightly wet (Ex. 2) 500° C. paste)25 HYPR monetite 7M NaOH 1/1/1 <30 min (Ex. 15) + RPR Alk. Sol'n + 20%(claylike sl. set (Ex. 2) 500° C. PAA paste) 26 HYPR monetite 7M NaOH1/1/1 35 min (Ex. 15) + RPR Alk. Sol'n + 5% (claylike (Ex. 2) 500° C.PAA paste) 27 HYPR monetite 7M NaOH 1/1/1.2 12-15 min (Ex. 15) + RPRAlk. Sol'n + 1% (slightly dry (Ex. 11)500° C. PAA paste) 28 HYPRmonetite 10 wt % 1/1/1.2 1 hr 15 min (Ex. 15) + RPR Ca(H₂PO₂)₂ (very wet(Ex. 1) 500° C. (aq) paste) 29 RPR 10 wt % 1.7/1 45 min (Ex. 11)500° C.Ca(H₂PO₂)₂ (very wet paste) ‘neat’ (aq) 30 RPR 10 wt % 2.5/1 20 min (Ex.11)500° C. Ca(H₂PO₂)₂ (sl. dry ‘neat’ (aq) paste/putty) 31 RPR 10 wt %2.25/1 15 min (Ex. 11)500° C. Ca(H₂PO₂)₂ + 1 wt % (very good ‘neat’H₂PO₂ (aq) paste/putty) 32 HYPR monetite 3.5 M NaOH 1/1/1 35 min. (Ex.15) + RPR Alk. Sol'n. (good *12 min. (Ex. 11)500° C. paste/putty) 33HYPR monetite 3.5 M NaOH 1/3/2 38 min. (Ex. 15) + RPR Alk. Sol'n.(paste/putty) *15 min. (Ex. 11)500° C. 34 HYPR monetite Saline, EDTA1/1/1 43 min. (Ex. 15) + RPR buffered (good *20 min. (Ex. 11)500° C.paste/putty)*= Set Time at 37° C., 98% Relative Humidity.HYPR monetite = HYdrothermally PROCESSED monetite (CaHPO₄).RPR = Reduction-oxidation Precipitation Reaction.^(#)45S5 glass = {24.5% CaO-24.5% Na₂O-6% P₂O₅-45% SiO₂ (wt %)}.PAA = Polyacrylic acid.Commercial β-TCP from Clarkson Chromatography Products, Inc. (S.Williamsport, PA)

Example 35 Low Temperature Neodymium Phosphate Powders

An aqueous solution of 11.04 g of 50 wt. % H₃PO₂ was diluted with 5.00 gdistilled water to form a clear, colorless solution contained in a 250ml fluoropolymer resin beaker on a hotplate/magnetic stirrer. Added tothis solution was 36.66 g neodymium nitrate hexahydrate salt,Nd(NO₃)₃-6H₂O (Alfa/Aesar reagent #12912, CAS # 16454-60-7), equivalentto 32.90 wt % Nd. The molar ratio of the Nd/P in this mixture was 1/1and the equivalent solids level (as NdPO₄) was 38.0 wt. %. Endothermicdissolution of the neodymium nitrate hexahydrate salt proceeded withgradual warming of the reaction mixture, eventually forming a clear,homogeneous lavender solution at room temperature. Heating of thissolution with constant agitation to approximately 70° C. initiated avigorous endothermic reaction which resulted in the evolution ofNO_(x(g)), rapid temperature increase of the sample to approximately100° C., and finally, formation of a pasty lavender mass. Heat treatmentof the pasty solid and subsequent X-ray diffraction analysis of thefired solid were conducted as described in Example 1. Results of theanalysis are as follows: $\begin{matrix}{{{Heated}\quad{to}\quad 500^{{^\circ}}\quad{C.}},{45\quad{minutes}}} & ({Major}) & {{Neodymium}\quad{phosphate}\quad{hydrate}} \\\quad & \quad & {\left\lbrack {{NdPO}_{4} - {0.5H_{2}O}} \right\rbrack\quad\left( {{{PDF}\quad 34} - 0535} \right)} \\{{{Heated}\quad{to}\quad 700^{{^\circ}}\quad{C.}},\quad{45\quad{minute}}} & ({Major}) & {{Monazite} - {{{Nd}\quad\left\lbrack {NdPO}_{4} \right\rbrack}\quad\left( {{{PDF}\quad 46} - 1328} \right)}}\end{matrix}$

Example 36 Low Temperature Cerium Phosphate Powders

An aqueous solution of 11.23 g of 50 wt. % H₃PO₂ was diluted with 5.00 gdistilled water to form a clear, colorless solution contained in a 250ml fluoropolymer resin beaker on a hotplate/magnetic stirrer. Added tothis solution was 36.94 g cerium nitrate hexahydrate salt, Ce(NO₃)₃-6H₂O(Johnson-Matthey reagent #11329-36), equivalent to 32.27 wt % Ce. Themolar ratio of the Ce/P in this mixture was 1/1 and the equivalentsolids level (as CePO₄) was 37.6 wt %. Endothermic dissolution of theneodymium nitrate hexahydrate salt proceeded with gradual warming of thereaction mixture, eventually forming a clear, homogeneous colorlesssolution at room temperature. Heating of this solution with constantagitation to approximately 65° C. initiated a vigorous endothermicreaction which resulted in the evolution of NO_(x(g)), rapid temperatureincrease of the sample to approximately >100° C., and finally, formationof a pasty light grey mass. Heat treatment of the pasty solid andsubsequent X-ray diffraction analysis of the fired solid were conductedas described in Example 1. Results of the XRD analysis are as follows:Heated to 700° C., 45 minutes (Major) Monazite-Ce [CePO₄] (PDF 32-0199)

Example 37 Low Temperature Yttrium Phosphate Powders

An aqueous solution of 14.36 g of 50 wt. % H₃PO₂ was diluted with 5.00 gdistilled water to form a clear, colorless solution contained in a 250ml fluoropolymer resin beaker on a hotplate/magnetic stirrer. Added tothis solution was 41.66 g yttrium nitrate hexahydrate salt, Y(NO₃)₃-6H₂O(Alfa/Aesar reagent #12898, CAS # 13494-98-9), equivalent to 23.21 wt %Y. The molar ratio of the Y/P in this mixture was 1/1 and the equivalentsolids level (as YPO₄) was 32.8 wt %. Endothermic dissolution of theyttrium nitrate hexahydrate salt proceeded with gradual warming of thereaction mixture, eventually forming a clear, homogeneous colorlesssolution at room temperature. Heating of this solution with constantagitation to approximately 75° C. initiated a vigorous endothermicreaction which resulted in the evolution of NO_(x(g)), rapid temperatureincrease of the sample to approximately >100° C., and finally, formationof a pasty white mass. Heat treatment of the pasty solid and subsequentX-ray diffraction analysis of the fired solid were conducted asdescribed in Example 1. Results of the XRD analysis are as follows:Heated to 700° C., 45 minutes (Major) Xenotime [YPO₄] (PDF 11-0254)

Example 38 Broad Applicabililty

A wide variety of minerals can be made in accordance with the presentinvention. In the following two tables, oxidizing and reducing agentsare listed. Any of the listed oxidants can be reacted with any of thelisted reducing agents and, indeed, blends of each may be employed.Appropriate stoichiometry will be employed such that the aforementionedreaction is caused to proceed. Also specified are possible additives andfillers to the reactions. The expected products are given as are some ofthe expected fields of application for the products. All of thefollowing are expected generally to follow the methodology of some orall of the foregoing Examples. Oxidizing Agents Reducing AgentsAdditives Product(s) Compounds of the form Oxoacids of Group 5B, 6B, andAl₂O₃, ZrO₂, TiO₂, SiO₂, Ca(OH)₂, XY(PO₄), XY(SO₄), XNO₃, where X = H,7B, (where 5B includes N, P, DCPD, DCPA, HAp, TCP, TTCP, XY(PO₄)(SO₄),Li, Na, K, Rb, Cs, and As; 6B includes S, Se, and MCMP, ZrSiO₄, W-metal,Fe metal, Ti WXYZ(PO₄)(SO₄)(CO₃), Cu, Ag, and Hg. Te; 7B includes Cl,Br, and I). metal, Carbon black, C-fiber or flake,WXYZ(PO₄)(SO₄)(CO₃)(F, Cl, Compounds of the form Phosphorous oxoacidCaF₂, NaF, carbides, nitrides, glass Br, I), WXYZ(PO₄)(SO₄) X(NO₃)₂,where X = Be, compounds: fibers, glass particulate, glass-ceramics,(CO₃)(F, Cl, Br, I)(OCl, OF, OBr, Mg, Ca, Sr. Ba, Cr, Mn, Hypophosphite(H₃PO₂); alumina fibers, ceramic fibers, OI), in the form of fiber,flake, Fe, Co, Ni, Cu, Zn, Rh, Hypophosphoric acid (H₄P₂O₆); bioactiveceramic fibers and whisker, granule, coatings, Pd, Cd, Sn, Hg, and PbIsohypophosphoric acid particulates, polyacrylic acid, polyvinylagglomerates and fine powders. (H₄P₂O₆); alcohol,polymethyl-methacrylate, Phosphonic acid or phosphorus polycarbonate,and other stable acid (H₃PO₃); polymeric compounds. Diphosphonic acid(H₄P₂O₅); Acetates, formates, lactates, simple Phosphinic acid orcarboxylates, and simple sugars. hypophosphorous acid (H₃PO₂). Compoundsof the form Sulfur oxoacid compounds: X(NO₃)₃ or XO(NO₃), Thiosulfuricacid (H₂S₂O₃); where X = Al, Cr, Mn, Dithionic acid (H₂S₂O₆); Fe, Co,Ni, Ga, As, Y, Polythionic acid (H₂S_(n + 2)O₆); Nb, Rh, In, La, Tl, Bi,Sulfurous acid (H₂SO₃); Ac, Ce, Pr, Nd, Steven Disulfurous acid(H₂S₂O₅); Meyer, Eu, Gd, Tb, Dy, Dithionous acid (H₂S₂O₄). Ho, Er, Tm,Yb, Lu, U, and Pu Compounds of the form X(NO₃)₄ or XO(NO₃)₂, where X =Mn, Sn, Pd, Zr, Pb, Ce, Pr, Tb, Th, Pa, U and Pu. Halogen oxoacids:perhalic acid (HOClO₃, HOBrO₃, HOIO₃); halic acid (HOClO₂, HOBrO₂,HOIO₂); halous acid (HOClO, HOBrO , HOIO)

The minerals prepared above may be used in a wide variety ofapplications. Examples of these applications may include, but are notlimited to, use as pigments, phosphors, fluorescing agents, paintadditives, synthetic gems, chromatography media, gas scrubber media,filtration media, bioseparation media, zeolites, catalysts, catalyticsupports, ceramics, glasses, glass-ceramics, cements, electronicceramics, piezoelectric ceramics, bioceramics, roofing granules,protective coatings, barnacle retardant coating, waste solidification,nuclear waste solidification, abrasives, polishing agents, polishingpastes, radiopharmaceuticals, medical imaging and diagnostics agents,drug delivery, excipients, tabletting excipients, bioactive dental andorthopaedic materials and bioactive coatings, composite fillers,composite additives, viscosity adjustment additives, paper finishingadditives, optical coatings, glass coatings, optical filters,fertilizers, soil nutrient(s) additives.

Example 39 Porous Shaped Bodies of Calcium Phosphates

An aqueous solution of 17.02 g 50 wt % hypophosphorous acid, H₃PO₂(Alfa/Aesar reagent #14142, CAS #6303-21-5), equivalent to 71.95 wt %[PO₄]⁻³ was combined with 5.00 g deionized water to form a clear,colorless solution contained in a 250 ml Pyrex beaker. To this solutionwas added 45.70 g calcium nitrate tetrahydrate salt, Ca(NO₃)₂.4H₂O (ACSreagent, Aldrich Chemical Co., Inc. #23,712-4, CAS #13477-34-4),equivalent to 16.97 wt % Ca. The molar ratio of [Ca]²⁺/[PO₄]⁻³ in thismixture was 3/2 and the equivalent solids level [as Ca₃(PO₄)₂] was 29.53wt %. Endothermic dissolution of the calcium nitrate tetrahydrateproceeded under ambient temperature conditions, eventually forming ahomogeneous solution. The viscosity of this solution was water-like,despite the high salt concentration.

A piece of damp (as removed from the packaging) cellulose sponge(O-Cel-O™, 3M Home and Commercial Care Division, P.O. Box 33068, St.Paul. MN 55133), trimmed to a block approximately 1.5″×1.5×″2.0″, wasimmersed in the calcium nitrate+hypophosphorous acid solution andkneaded (alternately compressed and decompressed) to fully imbibe thereactant solution into the sponge. The approximately 4.5 cubic inchsponge block (approximately 3.5 g), thoroughly saturated with reactantsolution (liquid uptake approximately 7 to 8 times the virgin spongeweight), was placed on a platinum plate in a laboratory furnace (Vulcanmodel 3-550, NEYTECH, Inc., 1280 Blue Hills Ave., Bloomfield, Conn.06002) that was preheated to 500° C. After several seconds, a reactioncommenced at the surface of the sponge with the evolution of red-brownfumes characteristic of NO_(x(g)). As the reaction proceeded from thesurface to the interior of the sponge block, NO_(x(g)) evolutioncontinued and some reactant liquid exuded from the sponge andaccumulated at the bottom of the Pt plate as a crusty white mass ofsolid. The cellulose sponge itself was consumed as the reactionprogressed and the reactant mass attained the oven temperature. Afterthermal treatment at 500° C. for 45 minutes, the sample was removed fromthe lab furnace. The sample had been converted to an inorganic replicaof the original organic sponge structure. The vestigial structurerepresented a positive version of the original sponge structure withfaithful replication of the cellular elements, porosity, andmacrostructure. The vestigial mass was mottled gray suggesting thepresence of some residual carbon in the structure due to incompleteburnout of the combustion products from the cellulose sponge matrix. Thevestigial mass was fragile with very low apparent density, but it wasrobust enough to be handled as a coherent block of highly porous solidonce it was removed from the exudate material.

An X-ray diffraction (XRD) pattern was obtained from a packed powdersample of the inorganic sponge material pulverized in a mortar andpestle. The pattern was obtained using a Rigaku MiniFlex instrument(Rigaku/USA, Inc., Northwoods Business Park, 199 Rosewood Dr., Danvers,Mass. 01923) running JADE pattern processing software (Materials Data,Inc., P.O. Box 791, Livermore, Calif. 94551) using a 2 degree/minutescan rate over the 2 theta angular range from 15-50°. The XRD patternfor this material is shown in FIG. 11. Peak analysis indicated the solidto consist of whitlockite Ca₃(PO₄)₂ (PDF 09-0169) and hydroxyapatiteCa₅(PO₄)₃(OH) (PDF 09-0432).

A sample of the O-Cel-O™ cellulose sponge was prepared for scanningelectron microscopy by sputter coating with Pt using a Hummer 6.2Sputtering System (Anatech, Inc., 6621-F Electronic Drive, Springfield,Va. 22151). SEM examination was performed using a JEOL model JSM-840Amicroscope (JEOL USA, Inc., 11 Dearborn Road, P.O. Box 6043, Peabody,Mass. 01961). FIG. 12 shows a SEM image of the virgin cellulose sponge.FIG. 13 shows a SEM image of the calcium phosphate material preparedfrom the cellulose sponge.

Example 40 Transformed Shaped Bodies of Calcium Phosphate

The material from Example 39 was fired under a variety of conditions inorder to (1) eliminate residual carbon from the structure and (2)attempt to promote sintering reactions in order to strengthen theinorganic sponge matrix. The samples were fired on Pt plates in aLindberg model 51333 box furnace (Lindberg/Blue M, Inc., 304 Hart St.,Watertown, Wis. 53094) equipped with a Lindberg series 59000 controlconsole. The following table summarizes these results: Temp./timeObservations XRD  900° C. 15 minutes Snow white mass 1000° C. 1 hourSnow white mass 1100° C. 1 hour Snow white mass 1100° C. 13 hours Snowwhite mass Whitlockite (FIG. 14) 1200° C. 13 hours Snow white mass 1350°C. 1 hour Snow white mass Whitlockite (FIG. 15)

A subjective assessment of the strength of these heat treated specimensshowed no apparent changes. There was no indication that sinteringoccurred even at temperatures up to 1350° C.

Example 41 Shaped Bodies

A solution was prepared as described in Example 39 using 9.70 g 5 wt %H₃PO₂, no deionized water, and 17.38 g Ca(NO₃)₂.4H₂O to obtain a molarratio of [Ca]²⁺/[PO₄]⁻³ of 1.0 and an equivalent solids level [asCaHPO₄] of 36.92 wt %. A small block of damp O-Cel-O™ sponge (as removedfrom the packaging) was fully imbibed with the reactant solution, set ina porcelain crucible, and placed into a Vulcan lab oven preheated to500° C. After 1 hour at 500° C., the mottled gray sample was refired at800° C. (Vulcan furnace) for 15 minutes. The final inorganic spongesample was completely white indicating complete carbon burnout. An XRDpattern (FIG. 16) was obtained from a packed powder sample prepared asdescribed in Example 39. Peak analysis indicated the solid to consist ofcalcium pyrophosphate, Ca₂P₂O₇ (PDF 33-0297).

Example 42 Shaped Bodies of Zinc Phosphate

An aqueous solution of 13.67 g 50 wt % H₃PO₂ was combined with 5.00 gdeionized water to form a clear, colorless solution contained in a 250ml Pyrex beaker. To this solution was added 46.23 g zinc nitratehexahydrate salt, Zn(NO₃)₂6H₂O (Aldrich Chemical Co., Inc. #22,873-7,CAS #10196-18-6), equivalent to 21.97 wt. % Zn. The molar ratio of[Zn]²⁺/[PO₄]⁻³ in this mixture was 3/2 and the equivalent solids level[as Zn₃(PO₄)₂] was 27.5 wt. %.

Endothermic dissolution of the zinc nitrate hexahydrate proceeded underambient temperature conditions, eventually forming a homogeneoussolution. A block of O-Cel-O™ sponge was fully imbibed with thisreactant solution as described in Example 39. The sample was first firedat 500° C. for 1 hour and then at 800° C. for 15 minutes. The inorganicsponge sample was light gray in color (due to residual carbon) and itwas robust enough to be handled as a coherent block of low density,highly porous material. An XRD pattern (FIG. 17) was obtained from apacked powder sample prepared as described in Example 39. Peak analysisindicated the solid to consist of zinc phosphate, Zn₃(PO₄)₂ (PDF30-1490).

Example 43 Neodymium Phosphate Bodies

An aqueous solution of 11.04 g 50 wt % H₃PO₂ was combined with 5.00 gdeionized water to form a clear, colorless solution contained in a 250ml Pyrex beaker. To this solution was added 36.64 g neodymium nitratehexahydrate salt, Nd(NO₃)₃,6H₂O (Alfa/Aesar reagent #12912, CAS#16454-60-7), equivalent to 32.90 wt % Nd. Endothermic dissolution ofthe neodymium nitrate hexahydrate proceeded under ambient temperatureconditions, eventually forming a pale lavender homogeneous solution. Ablock of O-Cel-O™ sponge was fully imbibed with this reactant solutionas described in Example 39. The sample was first fired at 500° C. for 1hour and then at 800° C. for 15 minutes. The inorganic sponge sample waspale lavender in color at the outside of the inorganic sponge mass andlight gray in the interior (due to residual carbon). The inorganicsponge mass was very fragile, but it was robust enough to be handled asa coherent block of low density, highly porous material. An XRD pattern(FIG. 18) was obtained from a packed powder sample prepared as describedin Example 39. Peak analysis indicated the solid to consist of neodymiumphosphate, NdPO₄ (PDF 25-1065).

Example 44 Aluminium Phosphate Bodies

An aqueous solution of 21.65 g 50 wt % H₃PO₂ was combined with 5.00 gdeionized water to form a clear, colorless solution contained in a 250ml Pyrex beaker. To this solution was added 61.56 g aluminum nitratenonahydrate salt, Al(NO₃)₃.9H₂O (Alfa/Aesar reagent #36291, CAS#7784-27-2), equivalent to 7.19 wt. % Al. Endothermic dissolution of thealuminum nitrate hexahydrate proceeded under ambient temperatureconditions, eventually forming a homogeneous solution. A block ofO-Cel-O™ sponge was fully imbibed with this reactant solution asdescribed in Example 39. The sample was first fired at 500° C. for 1hour and then at 800° C. for 15 minutes. The inorganic sponge sample waswhite at the outside of the inorganic sponge mass and light gray in theinterior (due to residual carbon). The inorganic sponge mass could behandled as a coherent block of low density, highly porous material. AnXRD pattern (FIG. 19) was obtained from a packed powder sample preparedas described in Example 39. Peak analysis indicated the solid to consistof aluminum phosphate, AlPO₄ (PDF 11-0500).

Example 45 Modified Porous Structures

A piece of the inorganic sponge material from Example 39 was immersed inmolten paraffin wax (CAS #8002-74-2) (Northland Canning Wax, ConrosCorp., Detroit, Mich. 48209) maintained at >80° C. so as to imbibe theporous structure. The inorganic sponge, wetted with molten wax, wasremoved from the molten wax and allowed to cool at room temperature. Thewax solidified on cooling and imparted additional strength and improvedhandling properties to the inorganic sponge material such that theparaffin wax-treated material could be cut and shaped with a knife. Mostof the formerly open porosity of the inorganic sponge material wasfilled with solidified paraffin wax.

Example 46 Gelatin Modification

A piece of the inorganic sponge material from Example 39 was immersed ina solution prepared by dissolving 7.1 g food-grade gelatin (CAS #9000-70-0) (Knox Unflavored Gelatin, Nabisco Inc., East Hanover, N.J.07936) in 100.0 g deionized water at approximately 90° C. The inorganicsponge material readily imbibed the warm gelatin solution and, afterseveral minutes, the largely intact piece of inorganic sponge materialwas carefully removed from the solution and allowed to cool and dryovernight at room temperature. The gelatin solution gelled on cooling(bloom strength unknown) and imparted additional strength and improvedhandling properties to the inorganic sponge material. Although no pH orelectrolyte/nonelectrolyte concentration adjustments were made to thesystem described in this example, it is anticipated that suchadjustments away from the isoelectric point of the gelatin would impartadditional rigidity to the gelatin gel and, thereby, to thegelatin-treated inorganic sponge material. Significant additionalstrength and improved handling properties were noted in thegelatin-treated inorganic sponge material after the gelatin was allowedto thoroughly dry for several days at room temperature. Some shrinkageof the gelatin-treated inorganic sponge materials was noted on drying.The shrinkage was nonuniform with the greatest contraction noted nearthe center of the body. This central region was, of course, the lastarea to dry and, as such, was surrounded by hardened inorganic spongematerial which could not readily conform to the contraction of the coreas it dehydrated. The material exhibited considerable improvement incompression strength and a dramatically reduced tendency to shedparticulate debris when cut with a knife or fine-toothed saw. It ispresumed that the film-forming tendency of the gelatin on drying inducedcompressive forces on the internal cellular elements of the inorganicsponge material, thereby strengthening the overall structure.

Cylindrical plugs could be cored from pieces of the air driedgelatin-treated inorganic sponge material using hollow punch toolsranging from {fraction (1/2)} inch down to {fraction (1/8)} inch indiameter.

FIG. 20 is a SEM of the air-dried gelatin treated inorganic sponge,which was prepared as described in Example 39. A comparison of this SEMwith that of the initial cellulose sponge material (FIG. 12) shows howfaithfully the sponge micro- and macrostructure has been replicated inthe inorganic sponge material. FIG. 21 is a SEM of sheep trabecularbone. The highly porous macrostructure of sheep trabecular bone isrepresentative of the anatomical structure of cancellous bone of highermammals, including humans. The sample of sheep trabecular bone wasprepared for SEM analysis by sputter coating (as described in Example39) a cross-sectional cut from a desiccated sheep humerus. FIG. 22 is ahigher magnification SEM of the air-dried gelatin treated inorganicsponge depicted in FIG. 20. From this SEM micrograph, the presence ofmeso- and microporosity in the calcium phosphate matrix is readilyapparent.

Example 47 Implant Cages

A rectangular block approximately {fraction (1/4)} inch×{fraction (1/2)}inch×{fraction (3/4)} inch was cut from a piece of damp (as removed fromthe packaging) O-Cel-O™ cellulose sponge. This sponge piece was trimmedas necessary so to completely fill the internal cavity of a titaniumnitride (TiN)-coated box-like spinal implant cage (Stratech Medical,Inc.). The sponge insert was intentionally made slightly oversized toensure good fit and retention in the cage assembly. The cellulose spongeblock was fully imbibed with a reactant solution prepared as describedin Example 39. The solution-saturated sponge insert was then insertedthrough the open side of the spinal cage assembly and manipulated tocompletely fill the interior cavity of the implant assembly. Despite thecompliance of the solution-saturated sponge, there was almost nopenetration of the sponge into the fenestrations of the implant. Thesponge-filled cage assembly, sitting on a Pt plate, was placed in alaboratory oven preheated to 500° C. and held at that temperature for 1hour. After cooling to room temperature, the implant assembly wasremoved from the small amount of crusty white solid resulting fromreactant solution which had exuded from the sponge insert and coated thesurface of the implant. The TiN coating on the cage appeared unaffectedby the treatment, and the internal chamber was filled with inorganicsponge material having a mottled gray appearance. The filled cageassembly was refired at 800° C. for 30 minutes in an attempt toeliminate residual carbon from the inorganic sponge material. Aftercooling, examination of the implant assembly revealed that the TiNcoating had been lost via oxidation, while the inorganic sponge materialwas completely white. There was excellent retention of the inorganicsponge material in the chamber of the spinal cage assembly.

Example 48 Orthopaedic Implants

Two cylindrical plugs of approximately {fraction (3/8)} inch diameterand {fraction (1/2)} inch length were cut from a piece of damp (asremoved from the packaging) Marquis™ cellulose sponge (distributed byFleming Companies, Inc., Oklahoma City, Okla. 73126) using a hollowpunch (Michigan Industrial Tools, P.O. Box 88248, Kentwood, Mich. 49518)of the appropriate size. These cellulose sponge plugs were then trimmedto the necessary length so to completely fill the bicompartmentalcentral cavity of a 13 mm×20 mm (diameter×length) BAK threadedcylindrical interbody implant (SpineTech, Inc., 7375 Bush Lake Road,Minneapolis, Minn. 55439). The plugs were intentionally made slightlyoversized to ensure good fit and retention in the two chambers of thetitanium spinal fusion cage assembly. The cylindrical sponge plugs werefully imbibed with a reactant solution prepared as described in Example39 and the solution saturated sponge plugs were inserted through theopen ends of the spinal cage assembly and manipulated to completely fillboth of the internal chambers of the implant assembly. Despite thecompliance of the solution-saturated sponge, there was almost nopenetration of the sponge into the fenestrations of the implant. Thesponge-filled cage assembly sitting on a Pt plate was placed in alaboratory oven preheated to 200° C. Immediately, a temperature ramp to500° C. was begun (duration of 16 minutes) followed by a 30 minute holdat 5000. After cooling to room temperature, the implant assembly wasremoved from the small amount of crusty white solid resulting fromreactant solution which had exuded from the sponge pieces and coated thesurface of the implant. The titanium cage appeared unaffected by thetreatment, and the chambers were filled with inorganic sponge materialhaving a mottled gray appearance. The filled cage assembly was refiredat 700° C. for 10 minutes in an attempt to eliminate residual carbonfrom the inorganic sponge material. After cooling, examination of theimplant assembly revealed that the surface of the titanium cage appearedto have undergone some oxidation as evidenced by its roughened texture,while the inorganic sponge material was white at the surface but stillgray at the center of the mass. Obviously, further heat treatment wouldbe necessary to fully oxidize the residual carbon in the interior of theinorganic sponge masses in each chamber of the implant assembly. Therewas excellent retention of the inorganic sponge material in both of thechambers of the spinal cage assembly.

Example 49 Sterilization

Samples of gelatin-treated inorganic sponge material were prepared asdescribed in Example 46 and allowed to thoroughly dry at roomtemperature for longer than one week. Pieces of this dry gelatin-treatedmaterial were subjected to prolonged oven treatments in an airatmosphere within a Vulcan model 3-550 oven (see Example 39) to simulateconditions typically encountered in “dry heat” sterilization procedures.The following table summarizes these experiments: Temperature (° C.)Time (h) Observations 130 3 No color change 130 6 Very slight yellowing130 15 Very slight yellowing 150 4 Very slight yellowing 170 1 Veryslight yellowing 170 3.5 Pale yellow at surface, white interior

It was assumed that temperature equilibration between the samples andthe oven was rapidly attained due to the significant porosity and lowthermal mass of the materials. Clearly, there was no significantdegradation of the gelatin under these heat treatment regimens.Furthermore, a subjective assessment of the strength of these dry heattreatment specimens showed no apparent changes.

Examples 50 Template Residues

A block of damp (as removed from the packaging) O-Cel-O™ brand cellulosesponge with a weight of 7.374 g, setting on a platinum plate, was placedinto a Vulcan model 3-550 oven preheated to 500° C. and held at thattemperature for 1 hour. At the conclusion of the burnout cycle, 0.073 gof fluffy gray ash was collected representing approximately 0.99 wt % ofthe original cellulose sponge mass.

A block of damp (as removed from the packaging) Marquis™ brand cellulosesponge with a weight of 31.089 g, setting on a platinum plate, wasplaced into a Vulcan model 3-550 oven preheated to 500° C. and held atthat temperature for 1 hour. At the conclusion of the burnout cycle,1.84 g of fluffy gray ash was collected representing approximately 5.9wt % of the original cellulose sponge mass. An XRD pattern obtained fromthis ash residue (FIG. 23) indicated the simultaneous presence ofmagnesium oxide, MgO (major) (PDF 45-0946) and sodium chloride, NaCl(minor) (PDF 05-0628) both phases resulting from the correspondingchloride salts used in the manufacturing process of the cellulosesponge. The presence of these two salts, in particular the MgO, mayaccount for the “incomplete” burnout of the inorganic sponge material at500 to 800° C. as noted in Examples 39, 41-44, 47, and 48.

Another block of the Marquis™ brand cellulose sponge was extensivelywashed in deionized water by repetitive kneading and multiple waterexchanges. This thoroughly washed sponge was allowed to dry in air atroom temperature for two days, after which it was cut into two blocks.The density of the washed and air-dried sponge comprising each of thesetwo blocks was calculated to be approximately 1.03 g/inch³. Each ofthese blocks of washed and air dried sponge was burned out according tothe aforementioned procedure. An insignificant amount of ash wascollected from each sample, indicating the efficacy of the washingprocedure for removing salt contaminants.

Example 51 Alternative Templates

A reactant solution was prepared as described in Example 39. A varietyof shapes, including disks, squares, and triangles, were cut from asheet of {fraction (3/32)} inch thick “Normandy compressed sponge”(Spontex, Inc., P.O. Box 561, Santa Fe Pike, Columbia, Tenn. 38402)using either scissors or hollow punches. This compressed cellulosesponge is manufactured to have a smaller median pore size and a narrowerpore size distribution than either of the commercially availablehousehold sponges (O-Cel-O™ or Marquis™) used in Examples 39-50. Thiscompressed sponge also has low ash levels (<0.1 wt % when burned outaccording to the procedure mentioned in Example 50) indicating that itis washed essentially free of salts during fabrication. The sponge iscompressed into a sheet which, upon rewetting, expands to restore theoriginal cellular sponge structure which, in the case of this particularexample, is approximately 1 inch thick. Imbibation of water into thecompressed sponge to saturation levels results in a weight increase ofapproximately 28 times over the dry sponge weight. The cut pieces ofcompressed sponge were fully imbibed with the reactant solution afterwhich they swelled to form cylinders, cubes, and wedges. These solutionsaturated sponge articles, setting on Pt plates, were placed into aVulcan model 3-550 oven preheated to 500° C. and held at thattemperature for 1 hour. After cooling, the inorganic sponge pieces werecarefully removed from the considerable amount of crusty white solidresulting from the exudate material. All samples had been converted toan inorganic replica of the original organic sponge structures. Thevestigial structures represented positive versions of the originalsponge structures with faithful replication of the cellular elements andporosity. The vestigial masses were fragile with very low apparentdensity, but they were robust enough to be handled as coherent blocks ofhighly porous solid once they were removed from the exudate material.The inorganic sponge material was mottled gray, suggesting the presenceof some residual carbon in the structure. After refiring the samples at800° C. (Vulcan furnace) for 15 minutes, the final inorganic spongesamples were completely white. The integrity of the various samples madefrom the controlled porosity cellulose sponge was improved overcorresponding samples prepared from the commercial cellulose spongematerials.

FIG. 24 is a SEM of the Normandy compressed sponge expanded in deionizedwater and prepared for microscopy as described in Example 39.

Example 52 Modified Templates

Pieces of the inorganic sponge material from Example 51 were immersed ina gelatin solution prepared as described in Example 46 except that 7.1 gof Knox gelatin was dissolved in 200 g deionized water rather than 100 gof deionized water. The inorganic sponge material readily imbibed thewarm gelatin solution and, after several minutes, the largely intactpieces of inorganic sponge material were carefully removed from thesolution and allowed to cool and dry at room temperature. Significantadditional strength and improved handling properties were noted in thegelatin-treated inorganic sponge material after the gelatin was allowedto thoroughly dry for several days. The material exhibited considerableimprovement in compression strength and a dramatically reduced tendencyto shed particulate debris when cut with a knife or fine-toothed saw.

Several pieces of gelatin treated sponge which had been drying in airfor >1 week were subjected to a burnout of the organic material at 800°C. (Vulcan furnace) for 30 minutes. The snow white inorganic spongesamples were weighed after firing and it was determined that the levelof gelatin in the treated samples was 13.8+/−1.0 wt % (with respect tothe inorganic sponge material).

FIG. 25 is a SEM of the air-dried gelatin treated inorganic sponge whichwas prepared as described above. A comparison of this SEM with that ofthe initial cellulose sponge material (FIG. 24) shows how faithfully thesponge micro- and macrostructure has been replicated in the polymercoated inorganic sponge material.

Example 53 Rewetting

Several pieces of air-dried gelatin-treated inorganic sponge materialfrom Example 46 were placed in deionized water to assess therewetting/rehydration behavior. Initially, the pieces floated at thewater surface but, after approximately 2 hours, the sponge pieces beganto float lower in the water indicating liquid uptake. After 24 hours,the samples were still floating, but >50% of the sponge volume was belowthe liquid surface. After 48 hours, the inorganic sponge samples werecompletely submerged suggesting complete rehydration of the gelatin andcomplete water ingress into the structure via interconnected porosity.

Example 54 Shaped Calcium Phosphates

Several pieces of the inorganic sponge material from Example 39 wereimmersed in a 50 wt % solution of disodium glycerophosphate hydrateprepared by dissolving 10.0 g C₃H₇O₆PNa₂ (Sigma Chemical Co. reagentG-6501, CAS # 154804-51-0), equivalent to 65.25 wt % as “Na₂PO₄”, in10.0 g deionized water. The inorganic sponge material readily imbibedthe disodium glycerophosphate solution and, after several minutes, thelargely intact pieces of saturated inorganic sponge material werecarefully removed from the solution. The wetted pieces, setting on a Ptplate, were placed in a Vulcan model 3-550 oven preheated to 150° C.Immediately, a temperature ramp to 850° C. was begun (duration of 50minutes) followed by a 60 minute hold at 850° C. After cooling to roomtemperature, the surface of the treated inorganic sponge material had aglassy appearance, and significant additional strength and improvedhandling properties were noted. Upon examination of the pieces with aLeica zoom stereo microscope, the presence of a glassy surface wasconfirmed and rounding of the features was evident indicating that somelevel of sintering had occurred. Considerable shrinkage of the pieceswas also noted.

An XRD pattern was obtained from a packed powder sample prepared asdescribed in Example 39. Peak analysis indicated the solid to consist,in part, of Buchwaldite, sodium calcium phosphate, NaCaPO₄ (PDF 29-1193and 29-1194).

Example 55 Discoid Bodies

A reactant solution was prepared as described in Example 39. Disks werecut from a sheet of {fraction (3/32)} inch thick Normandy compressedsponge using a {fraction (3/8)} inch diameter hollow punch and a modelno. 3393 Carver hydraulic press (Carver Inc., 1569 Morris St., P.O. Box544, Wabash, Ind. 46992) to ensure uniform sizing. The disks weredistended by immersion in deionized water and the resulting spongecylinders, each approximately {fraction (3/8)} inch diameter by 1 inchlength, were then blotted on paper towel to remove as much excess wateras possible. The damp sponge cylinders were then imbibed withapproximately seven times their weight of the reactant liquid. Nine ofthe solution imbibed pieces were placed horizontally and spaceduniformly in a 100×20 mm Pyrex petri dish. Two petri dishes, containinga total of 18 imbibed sponge cylinders, were positioned in the center ofthe cavity of a microwave oven (Hotpoint model no. RE963-001,Louisville, Ky. 40225) and the samples were irradiated at full power fora total of two minutes. After 30 seconds of exposure, the microwave ovencavity was full of NO_(x(g)) and the reactant liquid which had exudedfrom the sponge cylinders had reacted/dehydrated to form a crusty whitedeposit in the petri dishes. The oven was opened to vent the cavity,then full power irradiation was resumed. After another 30 seconds ofexposure, the oven cavity was again full of NO_(x(g)) and steam. Afterventing the cavity once more, full power exposure was resumed for anadditional 60 seconds, after which the fully dry sponge cylinders wereremoved. The sponge cylinders retained the orange color of the originalcellulose material and a considerable fraction of the pores were filledwith white solid. The pieces were very robust at this point, there waslittle or no warpage or slumping, and they could be handled and evenabraded to shape the pieces and to remove asperities and any adherentsolid resulting from the exuded liquid. The dried, solid-filledcylindrical sponge pieces were arrayed in a rectangular alumina crucible(2½″ W×6″ L×1/2″ D) and placed in a furnace preheated to 500° C. Thefurnace temperature was ramped at 40° C./minute to 800° C. and held at800° C. for 45 minutes. The resultant cylindrical white porous inorganicsponge samples were robust and exhibited strengths qualitatively similarto those attained from the fully dried gelatin-treated samples preparedas described in Example 52.

An XRD pattern was obtained from a packed powder sample prepared fromthe material fired at 800° C. Peak analysis indicated the solid toconsist solely of whitlockite, beta-Ca₃(PO₄)₂ (PDF 09-0169).

Example 56 Implantation of Calcium Phosphate Shaped Plug into CanineMetaphyseal Bone

The porous calcium phosphate scaffolds, prepared as described in Example55, are instantly wetted by water, aqueous solutions, alcohols, andother hydrophilic liquids in distinct contrast to the gradual rewettingof the gelatin-treated scaffold structure (Example 53). Blood readilywicks into the porous calcium phosphate bodies without obviousdetrimental effects. It is believed that cells, e.g., fibroblasts,mesenchymal, stromal, marrow, and stem cells, as well as protein-richplasma and combinations of the aforementioned cells can also be imbibedinto the porous structures.

Highly porous calcium phosphate cylindrical plugs were prepared asdescribed in Example 55 starting with 10 mm discs punched from Normandycompressed sponge. The cylindrical porous bodies were dry heatsterilized in DualPeel™ self seal pouches (distributed by AllegianceHealthcare Corp., McGaw Park, Ill. 60085) at 125° C. for 8 hours.

An animal experiment was initiated at Michigan State University, wherebya 10.3 mm×25 mm defect was drilled into the right shoulder (greatertubercle) of mongrel dogs. The site was cleaned of bone fragments andthe site filled with blood (and marrow cells) as the site was centeredin metaphyseal bone. The scaffold implants were removed from theirsterile pouch and inserted into the defect site. Initial penetration tohalf of the 25 mm depth was easily achieved with little resistance.Slight pushing was required to insert the remainder of the implant intothe site, such that the top of the scaffold was flush with the corticalbone surface. During insertion, blood could be seen readily wicking upthe porous scaffold. After complete insertion of the implant, bloodcould be seen flowing throughout and around the scaffold. The implantintergrity was maintained with no fragmentation or breakage. Thecompatibility with blood and marrow was evident. The surgical site wasthen closed.

FIG. 26 shows the cylindrical implant with initial wicking of blood.FIG. 27 depicts implantation of the cylinder into the canine bone.

Example 57 Porous Shaped Bodies of Hydroxyapatite

The mineral phase of human bone consists primarily of compositionallymodified, poorly crystalline hydroxyapatite, Ca₅(PO₄)₃(OH). Thehydroxyapatite crystallographic structure is partially substituted bycarbonate anions (7.4 wt. %) as well as by metal cations present atfractional wt. % levels. Analysis of human bone [R. Z. LeGeros, “CalciumPhosphates in Oral Biology and Medicine,” Monographs in Oral Science,Vol. 15 (H. M. Myers, Ed.), p 110, Karger Press (1991)] indicates, forexample, that the principal trace cationic constituents are as follows:Na⁺ (0.9 wt. %), Mg²⁺ (0.72 wt. %), and Zn²⁺ (trace, assumed as 0.05 wt.%). Heretofore, it has been difficult, if not impossible, to synthesizehydroxyapatite mineral doped with cations to the appropriate levels soas to approximate bone mineral. A unique capability and distinctadvantage of the RPR method is the facile manner in which precursorsolutions containing mixed metal ions can be prepared and converted intosolid phases via the redox precipitation reaction and subsequent thermalprocessing.

A reactant solution was prepared by combining 7.88 g 50 wt. %hypophosphorous acid, H₃PO₂, with 5.00 g deionized water in a 250 mlPyrex beaker. To this solution was added 22.51 g calcium nitratetetrahydrate salt, Ca(NO₃)₂.4H₂O; plus 0.33 g sodium nitrate salt, NaNO₃(Fisher Certified ACS reagent #S343-500, CAS #7631-99-4), equivalent to27.05 wt. % Na; plus 0.74 g magnesium nitrate hexahydrate salt,Mg(NO₃)₂.6H₂O (Alfa/Aesar reagent #11564, CAS 13446-18-9), equivalent to9.48 wt. % Mg; plus 0.046 g Zn(NO₃)₂,6H₂O (ACS reagent, Aldrich ChemicalCo., Inc. #22,873-7, CAS 10196-18-6), equivalent to 21.97 wt. % Zn.Endothermic dissolution of the salts proceeded with stirring and gradualwarming on a laboratory hot plate to approximately 20° C., eventuallyforming a homogeneous solution with a water-like viscosity despite thehigh salt concentration. The equivalent solids level (as cationsubstituted hydroxyapatite) was 27.39 wt. % and the target solidcomposition was 38.19 wt. % Ca, 0.90 wt. % Na, 0.70 wt. % Mg, 0.10 wt. %Zn, 56.72 wt. % PO₄, and 3.39 wt. % OH.

Eighteen 3/8-inch diameter×1-inch length cylinders of Normandy spongewere imbibed with this reactant liquid to approximately seven timestheir initial weight and microwave processed as described in Example 55.The dried, solid-filled cylindrical sponge pieces were then firedaccording to the procedure described in Example 55. The resultantcylindrical white porous inorganic scaffold samples were robust andsubjectively equivalent in strength to the articles produced in Example55.

An XRD pattern, FIG. 28, was obtained, as described in Example 39, froma packed powder sample of the material fired at 800° C. Analysis of bothpeak position and relative intensities over the angular range from 10 to60 degrees (2-theta) indicated the solid to consist of hydroxyapatite(PDF 09-0432). Additionally, four unassigned peaks at 29.9, 31.3, 34.7,and 47.4 degrees (2-theta) were observed in this sample. These are,presumably, due to the cationic substitutions leading to a distortedhydroxyapatite lattice structure.

The inorganic porous material prepared in Examples 39 through 57,derived from the precursor aqueous solutions involving the minerals ormaterials described in the preceding Examples 1 though 38, can beutilized in a variety of applications. These applications include, butare not limited to: bone or teeth replacement, filters, catalyticconverters, catalytic substrates, bioseparations media, pharmaceuticalexcipients, gas scrubber media, piezoelectric ceramics, pharmaceuticaldrug delivery systems, or aerators. As the examples illustrate, thecomposition can be easily tailored to accommodate the particular end usewithout the concerns of extensive material preparation such aspurification or particle size treatment. Further, the porous inorganicmaterial can be formed into a variety of practical shapes withoutelaborate tools or machining.

EXAMPLE 58 Composite Members for Reconstructive Use

A composite structure in accordance with this invention can be formedfrom an RPR material and from polymerizable material. A shaped structureis molded from an RPR material, especially one which gives rise tocalcium phosphate. Any of the foregoing methods for preparing shapedbodies of RPR can be used in this context. Thus, for example, an RPRcalcium phosphate is molded in the shape of an elongated rectangularprism. The shape is preferably purged of any cellulosic or othermaterial used in its formation and is rinsed of acidic residues andrendered sterile.

The shaped calcium phosphate is then coated with hardenable materialsuch as any of the polymerizable systems described heretofore. It ispreferred that the polymerizable material be an acrylic system havinginorganic fillers, especially where such fillers comprise at least aportion of Combeite to render the same bioactive. The hardenablematerial is then hardened either through thermal or photochemicalmechanisms or otherwise.

The resulting composite structure has a core of RPR material surroundedby a layer of hard polymer, preferably a polymer exhibiting bioactivity.As will be apparent, this structure mimics e mammalian bone, having atrabecular internal structure surrounded by a cancellous, hard exterior.Such structures may be elaborated in a very wide array of shapes for usein orthopaedic and other surgical restorations and reconstructions. Onparticular use is in the preparation of vertebral appliances such acages, rings spacers and spinal devices of many kinds. An additional useis in the preparation of materials for structural bone repair and telike. Thus, it can be seen that the RPR material which forms the overallshape of the structure can be molded or otherwise formed into a widevariety of shapes and, indeed, may be formed “to order” in an operatingroom. Thus, RPR materials can be milled or carved from a preformed blockto precisely match a prepared location for surgical reconstruction. Theshaped RPR material may then be coated with polymerizable material inany number of ways and the polymer cured, especially via actinic light.The coating with polymerizable material may be accomplished via dipping,spraying, painting, extrusion, sculpting, or, in short, in anyconvenient way amenable to the polymerizable material being used.

While the polymerizable material can be thermally cured, such as whentwo-paste systems are employed, actinic light curing systems arepreferred. Such actinic light curing is widely practiced in dentalrestoration and its techniques are well-known and can be easily modifiedto the practice of this invention. The preparation of the restorationcan be-accomplished in a matter of minutes, minimizing operative time.The restoration comprising the composite structures of this invention isapplied to a prepared site and preferably adhered therein. For thispurpose, polymerizable adhesives in the form of pastes, putties orliquids are employed, especially those formed from acrylic systems. Mostpreferred are acrylic cements and putties including fillers havingbioactive fillers, especially Combeite. In accordance with somepreferred embodiments, cement access orifices are provided in thecomposite shaped bodies of the invention. Such holes permit goodpenetration of adhesive or cements and may offer superior performance.

It will be appreciated that the polymerizable material coated upon theRPR material may be all or partially polymerized in situ to either servethe adhesive function or to assist therein. It can be convenient toapply two or more layers of polymerizable material to the RPR structurefor diverse purposes. Indeed, several different polymerizable systemsmay be employed. Thus, one layer or coating may be applied for strength,another for biocompatibility and a third for adhesive purposes. Otherfunctions or combinations may be employed.

The composite structures of this invention can mimic natural bonestructure. It is believed that the presence of an open trabecularstructure provided by the RPR material together with the hard, strongstructure mimicking cance/lous bone as can be provided by acrylicpolymers gives rise to superior results in use. Thus, the restorativecomposite structures are immediately weight bearing, while theirtrabecular structure provides less mass and confers some resilience tothe restoration. This composite structure provides restorations whichare easily accepted by natural bone and which does not overly stressnatural structures.

It will be appreciated that the methods for accomplishing the particularsteps described above are well known to persons of ordinary skill in theart in view of the present specification, of U.S. Pat. Nos. 5,681,872and 5,914,356 and the specifications of United States Serial Numbers784,439 filed Jan. 16, 1997; 011,219 filed Dec. 12, 1997; and 253,556filed Feb. 19, 1999; incorporated herein by reference.

EXAMPLE 59 Reinforced Composite Members

A composite member for reconstructive use can be prepared in accordancewith the previous example, but with the inclusion of reinforcements.Thus, an RPR shape is molded, extruded, or otherwise formed surroundingor substantially surrounding one or more rods or other reinforcements.The resulting structure is, itself, a composite structure in accordancewith the invention. It is preferred, however, to further elaborate uponthe structure by applying to it polymerizable material for subsequentcuring and use. It will be understood that reinforcement may take theform of metallic, ceramic, glass, polymeric or other structures withinor upon one of the portions of the composite structures of thisinvention and that such reinforcement may be included for purposes ofstrength, durability, biostimulation, biocompatibility, drug delivery,biopharmaceutical delivery or many other functions.

EXAMPLE 60 Complex Composite Members

A shape is molded from acrylic polymer filled with silanated microfinesilica in accordance with conventional techniques. The shape is selectedto closely mimic a lachrymal bone in an adult human. The molded shape iscoated with calcium phosphate RPR precursor material, including acellulosic material to form a viscous putty-fluid. The RPR reaction iscaused to occur and the resulting RPR material is heated, washed andotherwise treated as the practitioner may desire. The resultingstructure comprises the acrylic shape coated with RPR materia, the wholetaking the overall shape of the original acrylic body. A plurality ofholes are drilled in the body (or were present in the original moldedform). A further polymer-forming mixture is then applied to the shapedbody to coat all or a portion of it. The same is polymerized yielding a“three layer sandwich” arrangement of polymer core, RPR layer andpolymer top coating. The materials are selected such that the overallstructure is strong, but somewhat flexible. Upon application of crushingforce, the structure crushes rather than shatters. Accordingly, whenused in facial reconstruction, the bone replacement thus formed willcrush and deform, rather than shatter into potentially lethal shards.

EXAMPLE 61 Composite Catalytic Structures

Helices, tori, Raschig rings, microtubes and other structures for use inpacking chemical processing vessels, columns and the like can be formedin accordance with the invention. Thus, metallic shapes are formed inthe desired configuration and coated with RPR material. Since RPRmaterials can be formed in a very wide variety of chemical forms andstructures, extraordinary flexibility in the provision of suchstructures can be accomplished. Thus, structures having platinum,nickel, nickel alloys, palladium, copper, iron and many other chemicalmoieties may be exposed to chemical processes in a solid, easilyfilterable or, indeed, stationary form. Diverse catalytic and separatoryfunctions may be accomplished with such structures.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof and,accordingly, reference should be made to the appended claims rather thanto the foregoing specifications, as indicating the scope of theinvention.

1-20. cancel
 21. A vertebral ring comprising: an outer segment at leastpartially contacted by a inner segment comprising a material havingsubstantially uniform macro-, meso-, and microporosity together with apore volume of at least about 30%.
 22. The vertebral ring of claim 21wherein the inner segment is inorganic.
 23. The vertebral ring of claim21 wherein said inner segment material comprises calcium phosphate. 24.The vertebral ring of claim 21 wherein said outer segment comprises apolymerizable matrix.
 25. The vertebral ring of claim 21 wherein theouter segment comprises metal.
 26. The vertebral ring of claim 21wherein the outer segment comprises titanium.
 27. The vertebral ring ofclaim 21 wherein the vertebral ring comprises therapeutic materials,medicaments, or bone marrow aspirate.
 28. The vertebral ring of claim 21wherein the inner segment is imbibed with therapeutic materials,medicaments, or bone marrow aspirate.
 29. An interbody fusion devicecomprising: an outer segment at least partially contacted by a innersegment comprising a material having substantially uniform macro-,meso-, and microporosity together with a pore volume of at least about30%.
 30. The interbody fusion device of claim 29 wherein the innersegment is inorganic.
 31. The interbody fusion device of claim 29wherein the inner segment material comprises calcium phosphate.
 32. Theinterbody fusion device of claim 29 wherein the outer segment comprisesmetal.
 33. The interbody fusion device of claim 29 wherein the outersegment comprises titanium.
 34. The interbody fusion device of claim 29wherein the vertebral ring comprises therapeutic materials, medicaments,or bone marrow aspirate.
 35. The interbody fusion device of claim 29wherein the inner segment is imbibed with therapeutic materials,medicaments, or bone marrow aspirate.
 36. A shaped body comprising: anouter sleeve at least partially contacted by an inner segment comprisinga material having substantially uniform macro-, meso-, and microporositytogether with a pore volume of at least about 30%.
 37. The shaped bodyof claim 36 wherein the inner segment material comprises an inorganicmaterial.
 38. The shaped body of claim 36 wherein the inner segmentmaterial comprises calcium phosphate.
 39. The shaped body of claim 36wherein the sleeve comprises metal.
 40. The shaped body of claim 36wherein the sleeve comprises titanium
 41. The shaped body of claim 36comprising therapeutic materials, medicaments, or bone marrow aspirate.42. The shaped body of claim 36 wherein the inner segment is imbibedwith therapeutic materials, medicaments, or bone marrow aspirate.